Methods and devices for cryogenic carotid body ablation

ABSTRACT

Methods and cryogenic devices for assessing, and treating patients having sympathetically mediated disease, involving augmented peripheral chemoreflex and heightened sympathetic tone by reducing chemosensor input to the nervous system via carotid body ablation. Some methods include advancing a cryo-ablation catheter into a patient&#39;s vasculature and ablating tissue within a carotid septum.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/226,601, filed Aug. 2, 2016, which is a continuation of U.S.application Ser. No. 13/908,853, filed Jun. 3, 2013, now U.S. Pat. No.9,402,677, which claims priority to the following applications: U.S.Prov. App. No. 61/654,221, filed Jun. 1, 2012; U.S. Prov. App. No.61/666,384, filed Jun. 29, 2012; and U.S. Prov. App. No. 61/798,847,filed Mar. 15, 2013. The disclosures of all of the aforementionedapplications are incorporated by reference herein.

This application is related to the following applications, thedisclosures of which are incorporated by reference herein: U.S.application Ser. No. 13/852,895, filed Mar. 28, 2013; and U.S.application Ser. No. 13/869,765, filed Apr. 24, 2013, now U.S. Pat. No.9,393,070.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

The present disclosure is directed generally to cryogenic systems andmethods for treating patients having sympathetically mediated diseaseassociated at least in part with augmented peripheral chemoreflex orheightened sympathetic activation by ablating at least one peripheralchemoreceptor (e.g., carotid body).

BACKGROUND

It is known that an imbalance of the autonomic nervous system isassociated with several disease states. Restoration of autonomic balancehas been a target of several medical treatments including modalitiessuch as pharmacological, device-based, and electrical stimulation. Forexample, beta blockers are a class of drugs used to reduce sympatheticactivity to treat cardiac arrhythmias and hypertension; Gelfand andLevin (U.S. Pat. No. 7,162,303) describe a device-based treatment usedto decrease renal sympathetic activity to treat heart failure,hypertension, and renal failure; Yun and Yuarn-Bor (U.S. Pat. No.7,149,574; U.S. Pat. No. 7,363,076; U.S. Pat. No. 7,738,952) describe amethod of restoring autonomic balance by increasing parasympatheticactivity to treat disease associated with parasympathetic attrition;Kieval, Burns and Serdar (U.S. Pat. No. 8,060,206) describe anelectrical pulse generator that stimulates a baroreceptor, increasingparasympathetic activity, in response to high blood pressure; Hlavka andElliott (US 2010/0070004) describe an implantable electrical stimulatorin communication with an afferent neural pathway of a carotid bodychemoreceptor to control dyspnea via electrical neuromodulation. Morerecently, Carotid Body Ablation (CBA) has been conceived for treatingsympathetically mediated diseases.

SUMMARY OF THE DISCLOSURE

A method, device, and system have been conceived for cryo-ablation of acarotid body. Cryo-ablation of a carotid body generally refers todelivering a device with a cryo-ablation element in the region of itsdistal tip through a patient's body proximate to a peripheralchemosensor (e.g., carotid body) or an associated nerve of the patientand then activating the cryo-ablation element to ablate the tissuesurrounding the cryo-ablation element resulting in carotid bodyablation.

A carotid body may be ablated by placing a cryo-ablation element withinand against the wall of a carotid artery adjacent to the carotid body ofinterest, then activating the cryo-ablation element thereby lowering thetemperature of the periarterial space containing the carotid body to anextent and duration sufficient to ablate the carotid body.

A carotid body may also be ablated by placing a cryo-ablation elementwithin and against the wall of an internal jugular vein adjacent to thecarotid body of interest, then activating the cryo-ablation elementthereby lowering the temperature of the perivenous space containing thecarotid body to an extent and duration sufficient to ablate the carotidbody.

A carotid body may also be ablated by placing a cryo-ablation elementwithin and against the wall of a branch vein draining into a jugularvein, such as a facial vein, adjacent to the carotid body of interest,then activating the cryo-ablation element thereby lowering thetemperature of the perivenous space containing the carotid body to anextent and duration sufficient to ablate the carotid body.

A carotid body may also be ablated by placing a cryo-ablation elementwithin an extravascular space proximate to a carotid body of interest,then activating the cryo-ablation element thereby lowering thetemperature of the extravascular space containing the carotid body to anextent and duration sufficient to ablate the carotid body.

In another exemplary procedure a location of periarterial spaceassociated with a carotid body is identified, then a cryo-ablationelement is placed against the interior wall of a carotid artery adjacentto the identified location, then cryo-ablation parameters are selectedand the cryo-ablation element is activated thereby ablating the carotidbody, whereby the position of the cryo-ablation element and theselection of cryo-ablation parameters provides for ablation of thecarotid body without substantial collateral damage to adjacentfunctional structures.

In a further exemplary procedure a location of perivenous spaceassociated with a carotid body is identified, then a cryo-ablationelement is placed against the interior wall of an internal jugular veinadjacent to the identified location, then cryo-ablation parameters areselected and the cryo-ablation element is activated thereby ablating thecarotid body, whereby the position of the cryo-ablation element and theselection of cryo-ablation parameters provides for ablation of thecarotid body without substantial collateral damage to adjacentfunctional structures.

In a further exemplary procedure a location of extravascular spaceassociated with a carotid body is identified, then a cryo-ablationelement is placed proximate to the identified location, thencryo-ablation parameters are selected and the cryo-ablation element isactivated thereby ablating the carotid body, whereby the position of thecryo-ablation element and the selection of cryo-ablation parametersprovides for ablation of the carotid body without substantial collateraldamage to adjacent functional structures.

In further example the location of the periarterial space associatedwith a carotid body is identified, as well as the location of vitalstructures not associated with the carotid body, then a cryo-ablationelement is placed against the interior wall of a carotid artery adjacentto the identified location, cryo-ablation parameters are selected andthe cryo-ablation element is then activated thereby ablating the carotidbody, whereby the position of the cryo-ablation element and theselection of cryo-ablation parameters provides for ablation of thetarget carotid body without substantial collateral damage to vitalstructures in the vicinity of the carotid body.

In another example the location of the perivenous space associated witha carotid body is identified, as well as the location of vitalstructures not associated with the carotid body, then a cryo-ablationelement is placed against the interior wall of an internal jugular vein,or alternatively a facial vein adjacent to the identified location,cryo-ablation parameters are selected and the cryo-ablation element isthen activated thereby ablating the carotid body, whereby the positionof the cryo-ablation element and the selection of cryo-ablationparameters provides for ablation of the target carotid body withoutsubstantial collateral damage to vital structures in the vicinity of thecarotid body.

In another example the location of the extravascular space associatedwith a carotid body is identified, as well as the location of vitalstructures not associated with the carotid body, then a cryo-ablationelement is placed within or adjacent to the identified location,cryo-ablation parameters are selected and the cryo-ablation element isthen activated thereby ablating the carotid body, whereby the positionof the cryo-ablation element and the selection of cryo-ablationparameters provides for ablation of the target carotid body withoutsubstantial collateral damage to vital structures in the vicinity of thecarotid body.

In another example the location of the extravascular space associatedwith a carotid body is identified, as well as the location of vitalstructures not associated with the carotid body, then a cryo-ablationelement and an associated warming element is placed within or adjacentto the identified location, cryo-ablation and warming parameters areselected and the cryo-ablation element and warming element are thenactivated thereby cryo-ablating the carotid body while protecting vitalneural structures, by the position of the cryo-ablation element and theselection of cryo-ablation parameters in addition to the protectivewarming provides for ablation of the target carotid body withoutsubstantial collateral damage to vital structures in the vicinity of thecarotid body.

In another example the location of the extravascular space associatedwith a carotid body is identified, as well as the location of vitalstructures not associated with the carotid body, then a cryo-ablationelement is placed within or adjacent to the identified location, anextracorporeal high frequency focused ultrasound (HIFU) transducer isfocused on the location of vital structures not associated with thecarotid body that are proximate the identified location, cryo-ablationand HIFU parameters are selected and the cryo-ablation element and HIFUtransducer are then activated thereby cryo-ablating the carotid bodywhile protecting vital neural structures via selective warming withHIFU; by the position of the cryo-ablation element and the selection ofcryo-ablation parameters in addition to the protective warming providesfor ablation of the target carotid body without substantial collateraldamage to vital structures in the vicinity of the carotid body.

Selectable carotid body cryo-ablation parameters include cryo-ablationelement temperature, duration of cryo-ablation element activation,cryo-ablation element force of contact with a vessel wall, cryo-ablationelement size, cryo-ablation modality (reversible or not reversible),number of cryo-ablation element activations, and cryo-ablation elementposition within a patient.

The location of the perivascular space associated with a carotid body isdetermined by means of a non-fluoroscopic imaging procedure prior tocarotid body cryo-ablation, where the non-fluoroscopic locationinformation is translated to a coordinate system based onfluoroscopically identifiable anatomical and/or artificial landmarks.

A function of a carotid body is stimulated and at least onephysiological parameter is recorded prior to and during the stimulation,then the carotid body is cryo-ablated, and the stimulation is repeated,whereby the change in recorded physiological parameter(s) prior to andafter cryo-ablation is an indication of the effectiveness of thecryo-ablation.

A function of a carotid body is blocked and at least one physiologicalparameter(s) is recorded prior to and during the blockade, then thecarotid body is cryo-ablated, and the blockade is repeated, whereby thechange in recorded physiological parameter(s) prior to and aftercryo-ablation is an indication of the effectiveness of thecryo-ablation.

A device configured to prevent embolic debris from entering the brain isdeployed in an internal carotid artery associated with a carotid body,then a cryo-ablation element is placed proximate with the carotid body,the cryo-ablation element is activated resulting in carotid bodyablation, the cryo-ablation element is then withdrawn from the proximatelocation, then the embolic prevention device is withdrawn from theinternal carotid artery, whereby the device in the internal carotidartery prevents debris resulting from the use of the cryo-ablationelement from entering the brain.

A method has been conceived in which the location of the perivascularspace associated with a carotid body is identified, then a cryo-ablationelement is placed in a predetermined location against the interior wallof vessel adjacent to the identified location, then cryo-ablationparameters are selected and the cryo-ablation element is activated andthen deactivated, the cryo-ablation element is then repositioned in atleast one additional predetermined location against the same interiorwall and the cryo-ablation element is then reactivated using the same ordifferent cryo-ablation parameters, whereby the positions of thecryo-ablation element and the selection of cryo-ablation parametersprovides for ablation of the carotid body without substantial collateraldamage to adjacent functional structures.

A method has been conceived in which the location of the extravascularspace associated with a carotid body is identified, then a cryo-ablationelement is placed within the extravascular location or adjacent to theextravascular location, then cryo-ablation parameters are selected andthe cryo-ablation element is activated and then deactivated, thecryo-ablation element is then repositioned in at least one additionallocation and the cryo-ablation element is then reactivated using thesame or different cryo-ablation parameters, whereby the positions of thecryo-ablation element and the selection of cryo-ablation parametersprovides for ablation of the carotid body without substantial collateraldamage to adjacent functional structures.

A method has been conceived by which the location of the perivascularspace associated with a carotid body is identified, then a cryo-ablationelement configured for tissue freezing is placed against the interiorwall of a vessel adjacent to the identified location, then cryo-ablationparameters are selected for reversible cryo-ablation and thecryo-ablation element is activated, the effectiveness of the ablation isthen determined by at least one physiological response to the ablation,and if the determination is that the physiological response isfavorable, then the cryo-ablation element is reactivated using thecryo-ablation parameters selected for permanent carotid body ablation.

A method has been conceived by which the location of the extravascularspace associated with a carotid body is identified, then a cryo-ablationelement configured for tissue freezing is placed into or adjacent to theidentified location, an ultrasonic imaging device configured for imaginga boundary between frozen tissue and not frozen tissue in the locatedextravascular space is positioned for said imaging, cryo-ablationparameters are selected and the cryo-ablation element is activated whilethe tissue freezing is monitored by the ultrasonic imaging device, andthe cryo-ablation is deactivated when the boundary between frozen tissueand not frozen tissue approaches a predetermined boarder forcryo-ablation.

A system has been conceived comprising a vascular catheter configuredwith a cryo-ablation element in the vicinity of the distal end, and aconnection between the cryo-ablation element and a source ofcryo-ablation fluid at the proximal end, whereby the distal end of thecatheter is constructed to be inserted into a peripheral artery of apatient and then maneuvered into an internal or external carotid arteryusing standard fluoroscopic guidance techniques.

A system has been conceived comprising a catheter configured with acryo-ablation element in the vicinity of the distal end, and a means toconnect the ablation element to a source of cryo-ablation fluid at theproximal end, whereby the distal end of the catheter is constructed tobe inserted into a peripheral vein of a patient and then maneuvered intoan internal jugular vein, or alternately a facial vein using standardfluoroscopic guidance techniques.

A system has been conceived comprising a vascular catheter configuredwith a cryo-ablation element in the vicinity of the distal endconfigured for carotid body cryo-ablation and further configured for atleast one of the following: neural stimulation, neural blockade, carotidbody stimulation and carotid body blockade; and a connection between thecryo-ablation element and a source of cryo-ablation fluid, andstimulation energy and/or blockade energy.

A system has been conceived comprising a vascular catheter configuredwith a cryo-ablation element and at least one electrode configured forat least one of the following: neural stimulation, neural blockade,carotid body stimulation and carotid body blockade; and a connectionbetween the cryo-ablation element to a source of cryo-ablation fluid,and a connection between the cryo-ablation element and/or electrode(s)to a source of stimulation energy and/or blockade energy.

A system has been conceived comprising a vascular catheter with anablation element mounted in the vicinity of the distal end configuredfor tissue freezing, whereby, the ablation element comprises at leastone cryogenic expansion chamber and at least one temperature sensor, anda connection between the ablation element expansion chamber andtemperature sensor(s) to a cryogenic agent source, with the cryogenicagent source being configured to maintain the ablation element at apredetermined temperature in the range of 0 to −180 degrees centigradeduring ablation using signals received from the temperature sensor(s).System contains computer logic that controls delivery of cryogen inorder to maintain set temperature. Specifically temperature can be morethan one setting: (a) low cold setting in order to test response ofnerves, (b) high cold setting in order to cause ablation withconsequential destruction of tissue by necrosis and apoptosis of livingcells.

A system has been conceived comprising a probe configured forpercutaneous access to the extravascular space including a carotid bodywith a cryo-ablation element mounted in the vicinity of the distal endconfigured for tissue freezing, whereby, the cryo-ablation elementcomprises at least one cryogenic chamber and at least one temperaturesensor, and a connection between the cryogenic chamber and temperaturesensor(s) to a cryogenic fluid source, with the cryogenic fluid sourcebeing configured to maintain the cryo-ablation element at apredetermined temperature in the range of 0 to −180 degrees centigradeduring ablation using signals received from the temperature sensor(s).

A system has been conceived comprising a vascular catheter with anablation element mounted in the vicinity of the distal end configured tofreeze tissue, and to heat tissue, whereby, the ablation elementcomprises at least one cryogenic chamber constructed of an electricallyconductive material and configured as an electrode, and at least onetemperature sensor, and a connection between the ablation elementcryogenic chamber/electrode and temperature sensor(s) to an ablationsource consisting of cryogenic fluid source and an electrical heatingenergy source.

A system has been conceived comprising a probe configured forpercutaneous access to an extravascular space including a carotid bodywith an ablation element mounted in the vicinity of the distal endconfigured to freeze tissue, and to heat tissue, whereby, the ablationelement comprises at least one cryogenic chamber constructed of anelectrically conductive material and configured as an electrode, and atleast one temperature sensor, and a connection between the ablationelement cryogenic chamber/electrode and temperature sensor(s) to anablation source consisting of cryogenic fluid source and an electricalheating energy source.

A vascular cryo-ablation catheter has been conceived with a userdeflectable segment in the vicinity of the distal end and anon-deflectable segment proximal to the deflectable segment, where thedeflection of the distal segment is facilitated by a pull wire withinthe catheter in communication between the distal segment and a handlecontaining a deflection actuator at the proximal end, and acryo-ablation element mounted in the vicinity of the distal end, wherebythe deflection mechanism is configured to provide the user with a meansfor placing the cryo-ablation element against the wall of a vesseladjacent to a carotid body.

In accordance with another aspect of this invention is a vascularcatheter with a structure configured for user actuated radial expansionin the vicinity of the distal end, a radiopaque cryo-ablation elementmounted on one side of the structure and at least one radiopaque elementmounted on the opposite side of the structure, whereby the structureprovides the user with a means for pressing the cryo-ablation elementagainst the wall of a vessel, and the combination of the radiopaquecryo-ablation element and the radiopaque element provide the user with asubstantially unambiguous fluoroscopic determination of the location ofthe cryo-ablation element within the vessel.

A system for endovascular transmural cryo-ablation of a carotid body hasbeen conceived comprising an endovascular catheter with a cryo-ablationelement mounted in the vicinity of the distal end, a means for pressingthe cryo-ablation element against the wall of a carotid artery at aspecific location, a means for providing the user with a substantiallyunambiguous fluoroscopic determination of the position of the ablationelement in a carotid artery, a means for connecting the cryo-ablationelement to a source of cryogenic fluid mounted in the vicinity of theproximal end, and a console comprising a source of cryogenic fluid, ameans for controlling the cryogenic fluid, a user interface configuredto provide the user with a selection of cryo-ablation parameters,indications of the status of the console and the status of thecryo-ablation activity, a means to activate and deactivate acryo-ablation, and an umbilical to provide a means for connecting thecatheter to the console.

A method has been conceived to reduce or inhibit chemoreflex functiongenerated by a carotid body in a mammalian patient, to reduce afferentnerve sympathetic activity of carotid body nerves to treat asympathetically mediated disease, the method comprising: positioning acatheter in a vascular system of the patient such that a distal sectionof the catheter is in a lumen proximate to the carotid body of thepatient; pressing a cryo-ablation element against the wall of the lumenadjacent to the carotid body, supplying cryogenic fluid to thecryo-ablation element wherein the fluid is supplied by a fluid supplyapparatus outside of the patient; applying the fluid from the fluidsupply to the cryo-ablation element to ablate tissue proximate to orincluded in the carotid body; and removing the cryo-ablation device fromthe patient; wherein a carotid body chemoreflex function is inhibited orsympathetic afferent nerve activity of carotid body nerves is reduceddue to the ablation.

A method has been conceived to treat a patient having a sympatheticallymediated disease by reducing or inhibiting chemoreflex functiongenerated by a carotid body including steps of inserting a catheter intothe patient's vasculature, positioning a portion of the catheterproximate a carotid body (e.g., in a carotid artery), positioning acryo-ablation element toward a target ablation site (e.g., carotid body,intercarotid septum, carotid plexus, carotid sinus nerve), holdingposition of the catheter, applying cryogenic fluid to the cryo-ablationelement, and removing the catheter from the patient's vasculature.

The methods and systems disclosed herein may be applied to satisfyclinical needs related to treating cardiac, metabolic, and pulmonarydiseases associated, at least in part, with enhanced chemoreflex (e.g.,high chemosensor sensitivity or high chemosensor activity) and relatedsympathetic activation. The treatments disclosed herein may be used torestore autonomic balance by reducing sympathetic activity, as opposedto increasing parasympathetic activity. It is understood thatparasympathetic activity can increase as a result of the reduction ofsympathetic activity (e.g., sympathetic withdrawal) and normalization ofautonomic balance. Furthermore, the treatments may be used to reducesympathetic activity by modulating a peripheral chemoreflex.Furthermore, the treatments may be used to reduce afferent neuralstimulus, conducted via afferent carotid body nerves, from a carotidbody to the central nervous system. Enhanced peripheral and centralchemoreflex is implicated in several pathologies including hypertension,cardiac tachyarrhythmias, sleep apnea, dyspnea, chronic obstructivepulmonary disease (COPD), diabetes and insulin resistance, and CHF.Mechanisms by which these diseases progress may be different, but theycan commonly include contribution from increased afferent neural signalsfrom a carotid body. Central sympathetic nervous system activation iscommon to all these progressive and debilitating diseases. Peripheralchemoreflex may be modulated, for example, by modulating carotid bodyactivity. The carotid body is the sensing element of the afferent limbof the peripheral chemoreflex. Carotid body activity may be modulated,for example, by cryo-ablating a carotid body or afferent nerves emergingfrom the carotid body. Such nerves can be found in a carotid bodyitself, in a carotid plexus, in an intercarotid septum, in periarterialspace of a carotid bifurcation and internal and external carotidarteries, and internal jugular vein, or facial vein. Therefore, atherapeutic method has been conceived that comprises a goal of restoringor partially restoring autonomic balance by reducing or removing carotidbody input into the central nervous system.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration showing endovascular access of a catheter to aleft common carotid artery of a patient lying in supine position.

FIG. 2A is an illustration showing a percutaneous access needle beinginserted into the target region for carotid body ablation usingultrasonic imaging guidance.

FIG. 2B is an illustration showing a percutaneous cryo-ablation probe inposition for carotid body ablation with an ultrasonic imaging probebeing used to monitor the boundary of frozen tissue.

FIG. 3A is an illustration of a target region for carotid bodycryo-ablation showing the carotid body associated with an intercarotidseptum of a carotid bifurcation.

FIG. 3B is an illustration of a cross section of an intercarotid septum.

FIG. 4 is an illustration of a cross sectional view of a patient's neckshowing a percutaneous cryo-ablation probe in position for cryo-ablationof a carotid body.

FIG. 5 is a schematic view of a cryo-ablation catheter with two sideexiting guide wires.

FIG. 6 is a schematic view of a cryo-ablation catheter with a singleside exiting guide wire

FIG. 7 is a cutaway illustration of a lateral view of a patient's rightcarotid artery system with a schematic view of a cryo-ablation catheter,with side exiting guide wires, positioning a cryo-ablation element on aninner wall of a carotid bifurcation to transmurally cryo-ablate acarotid body while the boundary of the frozen tissue is monitored by anultrasonic imaging catheter positioned in the internal jugular vein.

FIG. 8 is a cutaway illustration of a lateral view a patient's rightcarotid artery system with a schematic view of a cryo-ablation catheter,with a side exiting guide wire, positioning a cryo-ablation element onan inner wall of an external carotid artery to transmurally cryo-ablatea carotid body while the boundary of frozen tissue is monitored by anextracorporeal ultrasonic imaging probe.

FIG. 9 is a schematic view of an endovascular cryo-ablation catheterhaving a side suction element with a cryo-ablation element.

FIG. 10 is a cutaway illustration of a lateral view a patient's rightcarotid artery system with a schematic view of an endovascularcryo-ablation catheter having a side suction element with acryo-ablation element positioned in an external carotid artery fortransmural cryo-ablation of a carotid body.

FIG. 11 is a schematic view of an endovascular cryo-ablation systemcomprising a suction fixation means.

FIG. 12 is a flow chart of an algorithm for operating an endovascularablation catheter having a suction element with a cryo-ablation element.

FIG. 13A is a schematic view of an endovascular catheter having adeployable balloon and a cryo-ablation element, in an undeployed state.

FIG. 13B is a schematic view of an endovascular catheter having adeployable balloon and a cryo-ablation element, in a deployed state.

FIGS. 13C(i), 13C(ii), 13C(iii), and 13C(iv) depict the cross sectionalviews from FIG. 13A.

FIG. 14 is a cutaway illustration of a lateral view a patient's rightcarotid artery system with a schematic view of an endovascularcryo-ablation catheter having a deployable balloon with a cryo-ablationelement positioned in the patient's external carotid artery fortransmural cryo-ablation of a carotid body.

FIGS. 15A and 15B are schematic views of an endovascular cryo-ablationcatheter configured for transmural cryo-ablation of a carotid body.

FIG. 16A is a schematic view of an endovascular ablation catheter havinga point-ablate cryogenic ablation element, contained in a steerablesheath, showing an ice ball formed around the cryogenic ablationelement.

FIG. 16B is a schematic view of a steerable endovascular ablationcatheter having a point-ablate cryogenic ablation element showing an iceball formed around the cryogenic ablation element.

FIG. 17 is a schematic view of an endovascular ablation catheter havinga point-ablate cryogenic ablation element.

FIG. 18 is a cutaway illustration of a lateral view a patient's rightcarotid artery system with a schematic view of an endovascular ablationcatheter having a point-ablate cryogenic ablation element, contained ina sheath, showing an ice ball formed around the cryogenic ablationelement.

FIG. 19A is a cutaway illustration of a lateral view of a patient'sright internal jugular vein with a schematic view of an endovascularcryo-ablation catheter positioned for transmural cryo-ablation of acarotid body from within the jugular vein.

FIG. 19B is a cross sectional view of a patient's internal and externalcarotid arteries, carotid body and internal jugular vein with anendovascular cryo-ablation catheter positioned for transmuralcryo-ablation of a carotid body from within the jugular vein where thedeflectable segment of the endovascular cryo-ablation catheter is usedto deform the jugular vein in order to position the cryo-ablationelement in close proximity to the carotid body.

FIG. 19C depicts a cryo-ablation of the carotid body.

FIG. 20 depicts a percutaneous cryo-ablation probe with a warmingelement at the distal tip.

FIG. 21 depicts a sectional view of percutaneous cryo-ablation probe inposition for carotid body cryo-ablation illustrating sympathetic nerveprotection using the probe's distal warming feature.

FIGS. 22A and 22B depict a schematic view of a cryo-ablation catheterhaving deployable arms that carry near critical cryogen.

FIG. 23 is a cutaway illustration of a lateral view of a patient's rightcarotid artery system with a schematic view of cryo ablation catheterdelivered through a delivery sheath and positioned at a patient'sintercarotid septum.

FIG. 24 is a schematic illustration of a cryo-ablation catheterdelivered through a balloon catheter that couples with a carotidbifurcation.

FIG. 25 is a schematic illustration of a cryo-ablation catheterdelivered through a balloon catheter that couples with a carotidbifurcation.

DETAILED DESCRIPTION

Cryogenic systems, devices, and methods have been conceived to ablatefully or partially one or both carotid bodies or peripheralchemoreceptors to treat patients having a sympathetically mediateddisease (e.g., cardiac, renal, metabolic, or pulmonary disease such ashypertension, CHF, or sleep apnea, sleep disordered breathing, diabetesor insulin resistance) at least partially resulting from augmentedperipheral chemoreflex (e.g., peripheral chemoreceptor hypersensitivity)or heightened sympathetic activation. A reduction of peripheralchemoreflex (e.g., chemosensitivity or afferent nerve hyperactivity) orreduction of afferent nerve signaling from a carotid body (CB) resultingin a reduction of central sympathetic tone is a main therapy pathway.Higher than normal chronic or intermittent activity of afferent carotidbody nerves is considered enhanced chemoreflex for the purpose of thisapplication regardless of its cause. Other important benefits such asincrease of parasympathetic tone, vagal tone and specifically baroreflexand baroreceptor activity reduction of dyspnea, hyperventilation andbreathing rate may be expected in some patients. Secondary to reductionof breathing rate additional increase of parasympathetic tone can beexpected in some cases. Augmented peripheral chemoreflex (e.g., carotidbody activation) leads to increases in sympathetic nervous systemactivity, which is in turn primarily responsible for the progression ofchronic disease as well as debilitating symptoms and adverse events seenin our intended patient populations. The patients are mammalianpatients, including humans. Carotid bodies contain cells that aresensitive to oxygen and carbon dioxide. Carotid bodies also respond toblood flow, pH acidity, glucose level in blood and possibly othervariables. Thus carotid body ablation may be a treatment for patients,for example having heart disease or diabetes, even if chemosensitivecells are not activated.

An inventive treatment, cryogenic carotid body ablation, may involveinserting a cryo-ablation device in to a patient, positioning a distalregion of the cryo-ablation device proximate a carotid body (e.g., in acommon carotid artery, internal carotid artery, external carotid artery,at a carotid bifurcation, proximate or in an intercarotid septum, in aninternal jugular vein), positioning an ablation element proximate to atarget site (e.g., a carotid body, an afferent nerve associated with acarotid body, a peripheral chemosensor, an intercarotid septum),optionally delivering non-ablative cryogenic energy from the ablationelement to temporarily block the target site, and delivering ablativecryogenic energy from the ablation element to ablate the target site.Other methods and devices for chemoreceptor ablation are described.

Targets:

To inhibit or suppress a peripheral chemoreflex, anatomical targets forcryo-ablation (also referred to as targeted tissue, target ablationsites, or target sites) may include at least a portion of at least onecarotid body, an aortic body, nerves associated with a peripheralchemoreceptor (e.g., carotid body nerves, carotid sinus nerve, carotidplexus), small blood vessels feeding a peripheral chemoreceptor, carotidbody parenchyma, chemosensitive cells (e.g., glomus cells), tissue in alocation where a carotid body is suspected to reside (e.g., a locationbased on pre-operative imaging or anatomical likelihood), anintercarotid septum, a substantial part of an intercarotid septum or acombination thereof. As used herein, ablation of a carotid body mayrefer to ablation of any of these target ablation sites.

An intercarotid septum 140 (also referred to as carotid septum) shown inFIGS. 3A and 3B is herein defined as a wedge or triangular segment oftissue with the following boundaries: A saddle of a carotid bifurcation4 defines a caudal aspect (an apex) of a carotid septum 140; Facingwalls of internal 16 and external 17 carotid arteries define two sidesof a carotid septum; A cranial boundary 141 of a carotid septum extendsbetween these arteries and may be defined as cranial to a carotid bodybut caudal to any vital nerve structures (e.g., hypoglossal nerve) thatmight be in the region, for example a cranial boundary may be about 10mm (possibly 15 mm) from the saddle of the carotid bifurcation 4; Medial142 and lateral 143 walls of the carotid septum 140 are generallydefined by planes approximately tangent to the internal and externalcarotid arteries; One of the planes 25 is tangent to the lateral wall ofthe internal and external carotid arteries and the other plane 24 istangent to the medial walls of these arteries. An intercarotid septum isbetween medial and lateral walls. An intercarotid septum 140 may containa carotid body 18 and may be absent of vital structures such as a vagusnerve 22 or vital sympathetic nerves 23 or a hypoglossal nerve 19. Anintercarotid septum may include some baroreceptors 202 or baroreceptornerves. An intercarotid septum may also include various nerves ofintercarotid plexus, small blood vessels 144 and fat 145.

Carotid body nerves are anatomically defined herein as carotid plexusnerves and carotid sinus nerves. Carotid body nerves are functionallydefined herein as nerves that conduct information from a carotid body toa central nervous system.

A cryo-ablation may be focused exclusively on targeted tissue, or befocused on the targeted tissue while safely ablating tissue proximate tothe targeted tissue (e.g., to ensure the targeted tissue is ablated oras an approach to gain access to the targeted tissue). An ablation maybe as big as the peripheral chemoreceptor (e.g., carotid body or aorticbody) itself, somewhat smaller, or bigger and can include tissuesurrounding the chemoreceptor such as blood vessels, adventitia, fascia,small blood vessels perfusing the chemoreceptor, or nerves connected toand innervating the glomus cells. An Intercarotid plexus or carotidsinus nerve maybe a target of ablation with an understanding that somebaroreceptor nerves will be ablated together with carotid body nerves.Baroreceptors are distributed in the human arteries and have high degreeof redundancy.

Tissue may be ablated to inhibit or suppress a chemoreflex of only oneof a patient's two carotid bodies. Another embodiment involves ablatingtissue to inhibit or suppress a chemoreflex of both of a patient'scarotid bodies. For example a therapeutic method may include ablation ofone carotid body, measurement of resulting chemosensitivity, sympatheticactivity, respiration or other parameter related to carotid bodyhyperactivity and ablation of the second carotid body if needed tofurther reduce chemosensitivity following unilateral ablation.

An embodiment of a therapy may substantially reduce chemoreflex withoutexcessively reducing the baroreflex of the patient. The proposedablation procedure may be targeted to substantially spare the carotidsinus, baroreceptors distributed in the walls of carotid arteries(specifically internal carotid artery), and at least some of the carotidsinus nerves that conduct signals from said baroreceptors. For example,the baroreflex may be substantially spared by targeting a limited volumeof ablated tissue possibly enclosing the carotid body, tissuescontaining a substantial number of carotid body nerves, tissues locatedin periadventitial space of a medial segment of a carotid bifurcation,or tissue located at the attachment of a carotid body to an artery. Saidtargeted ablation is enabled by visualization of the area or carotidbody itself, for example by CT, CT angiography, MRI, ultrasoundsonography, fluoroscopy, blood flow visualization, or injection ofcontrast, and positioning of an instrument in the carotid body or inclose proximity while avoiding excessive damage (e.g., perforation,stenosis, thrombosis) to carotid arteries, baroreceptors, carotid sinusnerves or other vital nerves such as vagus nerve or sympathetic nerveslocated primarily outside of the carotid septum. Thus imaging a carotidbody before ablation may be instrumental in (a) selecting candidates ifa carotid body is present, large enough and identified and (b) guidingtherapy by providing a landmark map for an operator to guide an ablationinstrument to the carotid septum, center of the carotid septum, carotidbody nerves, the area of a blood vessel proximate to a carotid body, orto an area where carotid body itself or carotid body nerves may beanticipated. It may also help exclude patients in whom the carotid bodyis located substantially outside of the carotid septum in a positionclose to a vagus nerve, hypoglossal nerve, jugular vein or some otherstructure that can be endangered by ablation. In one embodiment onlypatients with carotid body substantially located within the intercarotidseptum are selected for ablation therapy.

Once a carotid body is ablated, removed or denervated, the carotid bodyfunction (e.g., carotid body chemoreflex) does not substantially returnin humans (in humans aortic chemoreceptors are considered undeveloped).To the contrary, once a carotid sinus baroreflex is removed it isgenerally compensated, after weeks or months, by the aortic or otherarterial baroreceptor baroreflex. Thus, if both the carotid chemoreflexand baroreflex are removed or substantially reduced, for example byinterruption of the carotid sinus nerve or intercarotid plexus nerves,baroreflex may eventually be restored while the chemoreflex may not. Theconsequences of temporary removal or reduction of the baroreflex can bein some cases relatively severe and require hospitalization andmanagement with drugs, but they generally are not life threatening,terminal or permanent. Thus, it is understood that while selectiveremoval of carotid body chemoreflex with baroreflex preservation may bedesired, it may not be absolutely necessary in some cases.

Cryo-Ablation:

The term “cryo-ablation” may refer to the act of altering a tissue tosuppress or inhibit its biological function or ability to respond tostimulation permanently or for an extended period of time (e.g., greaterthan 3 weeks, greater than 6 months, greater than a year, for severalyears, or for the remainder of the patient's life) by removing heatenergy from tissue. Selective denervation may involve, for example,interruption of afferent nerves from a carotid body while substantiallypreserving nerves from a carotid sinus, which conduct baroreceptorsignals. Another example of selective denervation may involveinterruption of a carotid sinus nerve, or intercarotid plexus which isin communication with both a carotid body and some baroreceptors whereinchemoreflex from the carotid body is reduced permanently or for anextended period of time (e.g., years) and baroreflex is substantiallyrestored in a short period of time (e.g., days or weeks). As usedherein, the term “ablate” refers to interventions that suppress orinhibit natural chemoreceptor or afferent nerves functioning, which isin contrast to neuromodulating or reversibly deactivating andreactivating chemoreceptor functioning.

Cryogenic Carotid Body Ablation (CBA) herein refers to cryo-ablation ofa target tissue wherein the desired effect is to reduce or remove theafferent neural signaling from a chemosensor (e.g., carotid body) orreducing a chemoreflex. Chemoreflex or afferent nerve activity cannot bedirectly measured in a practical way, thus indexes of chemoreflex suchas chemosensitivity can sometimes be uses instead. Chemoreflex reductionis generally indicated by a reduction of an increase of ventilation andventilation effort per unit of blood gas concentration, saturation orpartial pressure change or by a reduction of central sympathetic nerveactivity that can be measured indirectly. Sympathetic nerve activity canbe assessed by measuring activity of peripheral nerves leading tomuscles (MSNA), heart rate (HR), heart rate variability (HRV),production of hormones such as renin, epinephrine and angiotensin, andperipheral vascular resistance. All these parameters are measurable andcan lead directly to the health improvements. In the case of CHFpatients, blood pH, blood PCO₂, degree of hyperventilation and metabolicexercise test parameters such as peak VO₂, and VE/VCO₂ slope are alsoimportant. It is believed that patients with heightened chemoreflex havelow VO₂ and high VE/VCO₂ slope (index of respiratory efficiency) as aresult of, for example, tachypnea and low blood CO₂. These parametersare also related to exercise limitations that further speed up patient'sstatus deterioration towards morbidity and death. It is understood thatall these indexes are indirect and imperfect and intended to directtherapy to patients that are most likely to benefit or to acquire anindication of technical success of ablation rather than to prove anexact measurement of effect or guarantee a success. It has been observedthat some tachyarrhythmias in cardiac patients are sympatheticallymediated. Thus carotid body ablation may be instrumental in treatingreversible atrial fibrillation and ventricular tachycardia.

Carotid body ablation may at least in part be due to alteration ofvascular or peri-vascular structures (e.g., arteries, arterioles,capillaries or veins), which perfuse the carotid body and neural fiberssurrounding and innervating the carotid body (e.g., nerves that transmitafferent information from carotid body chemoreceptors to the brain).Additionally or alternatively ablation may include tissue disruption dueto a healing process, fibrosis, or scarring of tissue followingcryogenic injury, particularly when prevention of regrowth andregeneration of active tissue is desired. Cryo-ablation may includereducing the temperature of target neural fibers below a desiredthreshold (e.g., to achieve freezing thermal injury). It is generallyaccepted that temperatures below −40° C. applied over a minute or tworesults in irreversible necrosis of tissue and scar formation. It isrecognized that tissue ablation by cold involves mechanisms of necrosisand apoptosis. At a low cooling rate freeze, tissue is destroyed bycellular dehydration and at high cooling rate freeze by intracellularice formation and lethal rupture of plasma membrane.

The mechanisms of cryotherapeutic tissue damage include, for example,direct cell injury (e.g., necrosis), vascular injury (e.g., starving thecell from nutrients by damaging supplying blood vessels), and sublethalhypothermia with subsequent apoptosis. Exposure to cryotherapeuticcooling can cause acute cell death (e.g., immediately after exposure)and/or delayed cell death (e.g., during tissue thawing and subsequenthyperperfusion).

In some embodiments, cryo-ablation of carotid body or carotid bodynerves may be achieved via direct application of thermal cooling totarget tissue. For example, a cryogenic element may be applied at leastproximate to the target, or cryogenic elements (e.g., cryogenicpoint-ablate tip, balloon, probe, cryo-tube) can be placed in a vicinityof a chemosensor (e.g., carotid body). Additional and alternativemethods and apparatuses may be utilized to achieve cryogenically inducedablation, as described hereinafter.

The devices described herein may also be used to temporarily stun orblock nerve conduction by cooling to non-ablative temperatures or atnon-ablative cooling rates. A temporary nerve block may be used toconfirm position of a cryo-ablation element prior to cryo-ablation. Forexample, a temporary nerve block may block nerves associated with acarotid body, which may result in a physiological effect to confirm theposition may be effective for cryo-ablation. Furthermore, a temporarynerve block may block vital nerves such as vagal, hypoglossal orsympathetic nerves that are preferably avoided, resulting in aphysiological effect (e.g., physiological effects may be noted byobserving the patient's eyes, tongue, throat or facial muscles or bymonitoring patient's heart rate and respiration). This may alert a userthat the position is not in a safe location. Likewise absence of aphysiological effect indicating a temporary nerve block of such vitalnerves in combination with a physiological effect indicating a temporarynerve block of carotid body nerves may indicate that the position is ina safe and effective location for carotid body ablation.

Cryo-ablation is a function of time as well as temperature. Thuscryogenic cooling can be applied to the ablation target site (e.g.,carotid body, carotid body nerves or carotid septum) and neural effectsmay be observed. If undesired neural effects are observed immediatelyafter cooling, cryo-ablation can be interrupted while the process ofablation is still in the reversible phase. If only desired effects areobserved, cooling can continue maintaining low temperature for aduration long enough to ensure irreversible cryo-ablation of affectedtissues.

Important nerves may be located in proximity of the target site and maybe inadvertently and unintentionally injured. Non-ablative cooling canhelp identify that these nerves are in the ablation zone before theirreversible ablation occurs. These nerves may include the following:

Vagus Nerve Bundle—The vagus is a bundle of nerves that carry separatefunctions, for example a) branchial motor neurons (efferent specialvisceral) which are responsible for swallowing and phonation and aredistributed to pharyngeal branches, superior and inferior laryngealnerves; b) visceral motor (efferent general visceral) which areresponsible for involuntary muscle and gland control and are distributedto cardiac, pulmonary, esophageal, gastric, celiac plexuses, andmuscles, and glands of the digestive tract; c) visceral sensory(afferent general visceral) which are responsible for visceralsensibility and are distributed to cervical, thoracic, abdominal fibers,and carotid and aortic bodies; d) visceral sensory (afferent specialvisceral) which are responsible for taste and are distributed toepiglottis and taste buds; e) general sensory (afferent general somatic)which are responsible for cutaneous sensibility and are distributed toauricular branch to external ear, meatus, and tympanic membrane.Dysfunction of the vagus may be detected by a) vocal changes caused bynerve damage (damage to the vagus nerve can result in trouble withmoving the tongue while speaking, or hoarseness of the voice if thebranch leading to the larynx is damaged); b) dysphagia due to nervedamage (the vagus nerve controls many muscles in the palate and tonguewhich, if damaged, can cause difficulty with swallowing); c) changes ingag reflex (the gag reflex is controlled by the vagus nerve and damagemay cause this reflex to be lost, which can increase the risk of chokingon saliva or food); d) hearing loss due to nerve damage (hearing lossmay result from damage to the branch of the vagus nerve that innervatesthe concha of the ear); e) cardiovascular problems due to nerve damage(damage to the vagus nerve can cause cardiovascular side effectsincluding irregular heartbeat and arrhythmia); or f) digestive problemsdue to nerve damage (damage to the vagus nerve may cause problems withcontractions of the stomach and intestines, which can lead toconstipation).

Superior Laryngeal Nerve—the superior laryngeal nerve is a branch of thevagus nerve bundle. Functionally, the superior laryngeal nerve functioncan be divided into sensory and motor components. The sensory functionprovides a variety of afferent signals from the supraglottic larynx.Motor function involves motor supply to the ipsilateral cricothyroidmuscle. Contraction of the cricothyroid muscle tilts the cricoid laminabackward at the cricothyroid joint causing lengthening, tensing andadduction of vocal folds causing an increase in the pitch of the voicegenerated. Dysfunction of the superior laryngeal nerve may change thepitch of the voice and causes an inability to make explosive sounds. Abilateral palsy presents as a tiring and hoarse voice.

Cervical Sympathetic Nerve—The cervical sympathetic nerve providesefferent fibers to the internal carotid nerve, external carotid nerve,and superior cervical cardiac nerve. It provides sympathetic innervationof the head, neck and heart. Organs that are innervated by thesympathetic nerves include eyes, lacrimal gland and salivary glands.Dysfunction of the cervical sympathetic nerve includes Homer's syndrome,which is very identifiable and may include the following reactions: a)partial ptosis (drooping of the upper eyelid from loss of sympatheticinnervation to the superior tarsal muscle, also known as Müller'smuscle); b) upside-down ptosis (slight elevation of the lower lid); c)anhidrosis (decreased sweating on the affected side of the face); d)miosis (small pupils, for example small relative to what would beexpected by the amount of light the pupil receives or constriction ofthe pupil to a diameter of less than two millimeters, or asymmetric,one-sided constriction of pupils); e) enophthalmos (an impression thatan eye is sunken in); f) loss of ciliospinal reflex (the ciliospinalreflex, or pupillary-skin reflex, consists of dilation of theipsilateral pupil in response to pain applied to the neck, face, andupper trunk. If the right side of the neck is subjected to a painfulstimulus, the right pupil dilates about 1-2 mm from baseline. Thisreflex is absent in Homer's syndrome and lesions involving the cervicalsympathetic fibers.)

Transmural Cryo-Ablation:

An endovascular catheter for transmural ablation may be designed andused to deliver an ablation element through a patient's vasculature toan internal surface of a vessel wall proximate a target ablation site. Acryo-ablation element may be, for example, a cryoablation balloon, apoint-ablate cryo-applicator, a flexible cryotube. The ablation elementmay be made from radiopaque material or comprise a radiopaque marker andit may be visualized using fluoroscopy to confirm position.Alternatively, a contrast solution may be injected through a lumen inthe ablation element to verify position. Cryo-ablation energy may bedelivered, for example from a source external to the patient such as acanister holding a cryogen or a console, to the cryo-ablation elementand through the vessel wall and other tissue to the target ablationsite. FIG. 1 depicts in simplified schematic form the placement of acarotid access sheath 1 into a patient 2 via an endovascular approachwith a femoral artery puncture. The sheath is depicted in position forinsertion of an endovascular transmural cryo-ablation catheter 3 intothe vicinity of the left carotid artery bifurcation 4 through a centrallumen of the carotid access sheath 1. A distal region of the sheath 5 isshown residing in the left common carotid artery 6. The proximal regionof the sheath 7 is shown residing outside of the patient 2, with thesheath's entry point into the patient 8 being in the vicinity of thegroin 9. From the sheath's entry point 8, the sheath enters a femoralartery 10, and traverses the abdominal aorta 11, the aortic arch 12, andinto the left common carotid artery 6. The carotid access sheath 1 maybe commercially available, or may be configured specifically forendovascular transmural cryo-ablation of a carotid body. The techniquesfor placing a carotid access sheath 1 into position as depicted areknown to those skilled in the art of endovascular carotid procedures.

Alternatively, an endovascular approach may involve access via a radialor brachial artery. In addition, the superficial temporal artery may bea potential access route to the external carotid artery at the level ofthe carotid bifurcation and carotid septum. Trans-superficial temporalartery access refers to puncturing a superficial temporal artery andinserting the distal end of an endovascular transmural carotid bodyablation catheter into the superficial temporal artery in a retrogradedirection and into the vicinity of the associated intercarotid septumfor the purpose of modulating a function of a carotid body.

A method has been conceived to reduce or inhibit chemoreflex generatedby a carotid body in a patient, to reduce afferent nerve sympatheticactivity of carotid body nerves to treat a sympathetically mediateddisease, the method comprising: inserting a catheter into a superficialtemporal artery of the patient in the retrograde direction, positioningthe catheter such that a distal section of the catheter adopted todelivery of cryogenic cooling is positioned in the external carotidartery proximate to a carotid body of the patient; pressing an ablationelement against the wall of an external carotid artery, and/or aninternal carotid artery adjacent to the carotid body, supplying coolingrefrigerant to the ablation element(s) wherein the refrigerant issupplied by an supply apparatus outside of the patient; applying thecryogenic energy to the ablation element(s) to ablate tissue proximateto or included in the carotid body; achieving cryoadhesion (contactfreezing, the bond between the external surface of the ablation elementand the tissue being treated; facilitated by moisture on the tissue) inorder to retain the energy element in the desired position adhering tothe wall of the external carotid artery, optionally rewarming thecryogenic element, and removing the ablation device from the patient;wherein a carotid body chemoreflex function is inhibited or sympatheticafferent nerve activity of carotid body nerves is reduced due to theablation.

Percutaneous Cryo-Ablation:

FIGS. 2A and 2B are illustrations of percutaneous access procedures forpercutaneous carotid body cryo-ablation. FIG. 2A shows an extracorporealultrasonic imaging transducer guiding insertion of percutaneous cannula14 into a target site for carotid body cryo-ablation. The cannula 14 mayhave an echogenic coating to facilitate visualization with sonography.The echogenic coating may include microbubbles of gas immobilized in thepolymeric coating. Once the cannula 14 is positioned with its distal endnear or in a target ablation site, for example as confirmed usingvisualization such as ultrasound sonography, a trocar may be removedfrom the cannula 14 and a cryo-ablation probe 15 may be inserted into alumen of the cannula 14 as shown in FIG. 2B. As shown, an operator isholding an ultrasonic imaging probe 13 against the skin on the neck.Alternatively, an imaging probe may incorporate a cannula guide in orderto facilitate cannula positioning and visibility by keeping it in planeof a monographic image.

Biplane transducer arrays that are rotated (for example 90 degrees)relative to each other (e.g., form a T shape) are used to allow a doctorto view two image planes at once. The purpose of biplane imaging is toenable doctor to visualize simultaneously the cannula or ablation needleand the carotid arteries. The imaging plane for visualization of carotidarteries or a jugular vein may include Doppler imaging modes such aspulsed wave Doppler mode. A color Doppler image of blood vessels canenable distinction of veins and arteries and assist navigation ofablation instruments into the carotid septum.

Optionally, once an initial cannula is placed in a desired location thechannel made in the tissue by the cannula may be dilated from a smalldiameter to a larger diameter cannula by exchanging the larger diametercannula over the smaller diameter cannula or over a wire. This mayprovide a larger working channel for a percutaneous ablation probe ifneeded while allowing the use of a smaller diameter cannula for initialplacement. Alternatively, a cryo-ablation probe may be inserted throughtissue to a target ablation site directly (e.g., without the use of acannula as shown in FIG. 2B).

FIG. 4 is a cross sectional illustration of a neck of a patient 2depicting a percutaneous cryo-ablation probe 15 ablating a carotid body18 and other tissue within an intercarotid septum 140, showing a zone offrozen tissue 40 between external carotid artery 17 and internal carotidartery 16. It may be desired to avoid injury of important non-targetnerves, for example a sympathetic nerve 23 or other important non-targetnerves located medially to the septum 140. Such nerves may be locatedjust outside of a medial plane of a carotid sheath. Jugular vein 20 mayobscure access to the carotid septum 140 with the straight cannula 14. Ajugular vein may be repositioned relative to carotid arteries 17 and 16by rotating of the patient's neck 26 or external manipulation of thevein.

Embodiments of Cryogenic CBA Devices:

FIG. 5 depicts the distal region of a carotid access sheath 1 withdistal region of an Endovascular Transmural Cryo-Ablation (ETCA)catheter comprising two side-exiting guide wire ports, which will herebybe referred to as the 2-Wire ETCA catheter 28, extending from thecentral lumen 124 of carotid access sheath 1. The 2-Wire ETCA catheter28 may comprise a cryo-ablation element 29 mounted in a vicinity of adistal end of the catheter, at least two side exiting guide wire ports32 and 33 in substantial diametric opposition to each other in thevicinity of the distal end, a catheter shaft 34 comprising at least twoguide wire lumens, not shown, in communication with guide wire ports 32and 33, a means to connect the cryo-ablation element 29 to a cryogenicfluid source in the vicinity of the proximal end, not shown, and a meansfor inserting a guide wire into the guide wire lumens at the proximalend consisting of female luer fittings or Touy Borst fittings, notshown. The 2-Wire ETCA catheter 28 is depicted here with two guide wires30 & 31 exiting guide wire ports 32 and 33. Guide wire ports 32 and 33may be configured such that guide wires 30 and 31 exit the guide wireports 32 and 33 at an angle of approximately 45 degrees as depicted, ormay be configured for a guide wire exit angle that is greater than orless than that depicted. Guide wire ports 32 and 33 and correspondinglumens may be configured for use with guide wires 30 and 31 between0.014″ and 0.018″ diameter. The distance of the guide wire ports fromthe distal tip may be fixed as depicted, or may be user selectable by adistance selection means, not shown. The distance between guide wireport 32 and the distal tip may be the same or different than thedistance between guide wire port 33 and the distal tip. The distancebetween the distal tip and either guide wire port 32 and 33 may beindependently selectable by the user. Cryo-ablation element 29 may beassociated with at least one temperature sensor, not shown. In additioncryo-ablation element 29 may also be configured for monopolar or bipolarRF ablation, neuroprotective warming, or tissue thawing. Catheter shaft34 may comprise at least one catheter shaft electrode 35 configured forelectrical neuro-modulation. Cryo-ablation element 29 may be configuredfor electrical neuro-modulation independently or in conjunction withcatheter shaft electrode(s) 35. The 2-Wire ETCA catheter 28 may beconfigured for use with a carotid access sheath 1 having a workinglength between 100 cm and 140 cm, and a diameter of 5 French to 8French. The techniques for constructing the 2-Wire ETCA catheter 28 asdepicted is familiar to those skilled in the art of catheter making, andtherefore are not further elaborated.

FIG. 6 depicts a distal end of a carotid access sheath 1 with anEndovascular Transmural Cryo-Ablation (ETCA) catheter comprising asingle side-exiting guide wire port 37, which will hereby be referred toas the Side-Wire ETCA catheter 36, extending from the central lumen 124of carotid access sheath 1. Side-Wire ETCA catheter 36 comprises acryo-ablation element 39 mounted in vicinity of a distal end, and a sideexiting guide wire port 37 in vicinity of the distal end but proximal tothe cryo-ablation element 39, catheter shaft 125 comprising a guide wirelumen, not shown, in communication with guide wire port 37, a connectorthat connects cryo-ablation element 39 to a cryogen fluid source in thevicinity of a proximal end, not shown, and a means for inserting a guidewire into the guide wire lumen at the proximal end consisting of femaleluer fitting or Touy Borst fitting, not shown. Side-Wire ETCA catheter36 is depicted here with guide wire 38 exiting guide wire port 37. Guidewire port 37 may be configured such that guide wire 38 exits guide wireport 37 at an angle of approximately 45 degrees as depicted, or may beconfigured for a guide wire exit angle that is greater than or less thanthat depicted. Guide wire port 37 and corresponding lumen may beconfigured for use with a guide wire between 0.014″ and 0.018″ diameter.The distance of the guide wire port 37 from the distal tip 126 may befixed as depicted, or may be user selectable by a distance selectionmeans, not shown. For example, the distance between a guide wire port 37and the distal tip 126 may be between about 10 to 20 mm, which mayposition a cryo-ablation element 39 at an ideal location on a carotidseptum to target a carotid body or its nerves for cryo-ablation.Cryo-ablation element 39 may be associated with at least one temperaturesensor, not shown. Cryo-ablation element 39 may also be configured formonopolar or bipolar RF ablation, neuroprotective warming, or tissuethawing. Catheter shaft 125 may comprise at least one catheter shaftelectrode 35 configured for electrical neuro-modulation. Cryo-ablationelement 39 may be configured for electrical neuro-modulationindependently or in conjunction with catheter shaft electrode(s) 35.Side-Wire ETA catheter 36 is configured for use with a carotid accesssheath 1 having a working length between 100 cm and 140 cm, and adiameter of 5 French to 8 French. The techniques for constructing theSide-Wire ETA catheter 36 as depicted is familiar to those skilled inthe art of catheter making, and therefore are not further elaborated.

FIG. 7 depicts in simplified schematic form the 2-Wire ETCA catheter 28in position for ablation of a carotid body 18 immediately following anablation. As depicted the distal tip of ablation element 29 ispositioned against a carotid bifurcation 4, with a guide wire 31 exitingside guide wire port 33 into the internal carotid artery 16, and asecond guide wire 30 exiting side port 32 into the external carotidartery 17 as shown. Guide wires 30 and 31 provide a means forpositioning and maintaining the distal tip of ablation element 29centered at the bifurcation 4 in a stable manner during ablation. Thecryo-ablation zone 40 of frozen tissue is depicted encompassing theperiarterial space comprising the carotid body 18. Also depicted is thecarotid access sheath 1 used for placement of the 2-Wire ETA catheter 28into the common carotid artery 6. Also, an optional intravascularultrasonic imaging catheter 41 configured for imaging the boundarybetween frozen tissue, and not frozen tissue is depicted residing ininternal jugular vein 20 with ultrasonic imaging beam 42 penetrating thecryo-ablation zone 40. Ultrasonic imaging provides the user with anindication that the zone of frozen tissue is, or is not within thedetermined boundary for safe cryo-ablation. Alternatively,extracorporeal ultrasound sonography may be used to visualize the zoneof frozen tissue.

FIG. 8 depicts in simplified schematic form Side-Wire ETCA catheter 36in position for ablation of a carotid body 18 immediately following acryo-ablation. As depicted cryo-ablation element 39 is positionedagainst the wall of the external carotid artery 17 at a position distalto the carotid bifurcation 4, which distance 45 as shown may bepredetermined prior to the placement of the Side-Wire ETCA catheter 36,or may be a distance suitable for positioning a cryo-ablation element 39proximate a majority of patients' carotid bodies and carotid body nervesrelative to carotid bifurcation 4, for example approximately 5 mm to 20mm. Guide wire 38 is shown exiting side guide wire port 37 into aninternal carotid artery 16. The guide wire 38 in conjunction with guidewire port 37 provide a means for positioning cryo-ablation element 39against a wall of an external carotid artery 17 at a predetermineddistance 45 based on the distance between the distal tip 126 and theguide wire port 37. The force of contact between cryo-ablation element39 and the wall of external carotid artery 17 can be influenced by theselection of the stiffness and/or diameter of the guide wire 38, theangle of exit of the guide wire 38, as well as the distance betweendistal tip 126 and guide wire port 37. The cryo-ablation zone 40 offrozen tissue is depicted encompassing the periarterial space comprisingthe carotid body 18. Also depicted is a carotid access sheath 1 used forplacement of Side-Wire ETCA catheter 36 into a common carotid artery 6.Also, an optional extracorporeal ultrasonic imaging probe 43 configuredfor imaging a boundary between frozen tissue, and not frozen tissue isdepicted imaging from the surface of the patient's neck 26 withultrasonic imaging beam 44 focused on an area around the cryo-ablationzone 40. Ultrasonic imaging provides a user with an indication that thezone of frozen tissue is, or is not within the determined boundary forsafe cryo-ablation. Ultrasonic imaging probe 43 may have Doppler flowdetection and visualization capability in order to assist an operator inmonitoring location of the ETCA catheter and blood flow in the carotidarteries.

FIG. 9 depicts the distal end of an Endovascular TransmuralCryo-Ablation Lateral Suction (ETCALS) catheter 46. ETCALS catheter 46comprises a catheter shaft 53, a cryo-ablation element 47 mounted in thevicinity of the distal end of the catheter shaft as shown, a lateralsuction cup 48 also mounted in the vicinity of the distal end of thecatheter shaft 53, and partially surrounding ablation element 47 asshown, a proximal terminal, not shown, comprising a cryogen fluidconnector, and a suction connector. Catheter shaft 53 comprises a lumenin fluidic communication between the lateral suction cup 48 and thesuction connector of the proximal terminal of the catheter locatedoutside of the body (not shown), and a cryogen fluid supply conduit anda cryogen fluid return conduit in fluidic communication withcryo-ablation element 47 and cryogen supply and return connectors at theproximal terminal. Catheter shaft 53 is fabricated from a polymer suitedfor catheter construction such as Pebax or polyurethane, and maycomprise a braided structure within its wall to provide torsionalrigidity while maintaining axial flexibility to aid in directionalpositioning of lateral suction cup 48. In addition, cryo-ablationelement 47 may be configured for monopolar or bipolar RF ablation,neuroprotective warming, or to thaw frozen tissue, monopolar or bipolarneural stimulation, or monopolar or bipolar neural blockade. Lateralsuction cup 48 is fabricated from an elastomer such as silicone rubberor polyurethane, and may have radiopaque markers 51 and 52 molded into awall, or disposed upon a wall using an adhesive. The number ofradiopaque markers, size, shape, and their positions provide the userwith a substantially unambiguous indication of the position of lateralsuction cup 48 within a carotid artery. Lateral suction cup 48 is bondedto the distal end of catheter shaft 53 with the ablation element 47substantially surrounded by lateral suction cup 48 except for ablationaperture 50. Lateral suction cup 48 may comprise a suction flange 49 tofacilitate suction fixation to the wall of a carotid artery duringcryo-ablation. The ETCALS catheter 46 is configured for use through acarotid access sheath, with a central lumen between 6 French and 12French, not shown. The working length of the ETCALS catheter may bebetween about 100 cm to 140 cm.

FIG. 10 depicts a, ETCALS catheter 46 in position for ablation of acarotid body 18 immediately following a cryo-ablation 40. The ETCALScatheter suction cup 48 is shown in position against the wall ofexternal carotid artery 17 immediately adjacent to carotid body 18 beingheld in place by suction applied to lateral suction cup 48 duringcryo-ablation element 47 activation.

FIG. 11 depicts in schematic form a system for carotid bodycryo-ablation using an ETCALS catheter 46. The system comprises anETCALS catheter 46, a carotid access sheath 1, control module 66, asuction module 61, a footswitch 65, and umbilical 57 that connects theETCALS catheter 46 to the control module 66. The control module 66comprises a source of cryogenic fluid, not shown, a means to controlcryo-ablation based on user selection of power control algorithms, andor by means of temperature control algorithms based on signals fromtemperature sensor(s) associated with cryo-ablation element 47, notshown, a means for controlling the suction module 61 in response tovacuum sensor 60, and foot switch 65, a user interface 68 that providesthe selection of cryo-ablation parameters, an indication of the statusof the system, a means to initiate an ablation, and a means to terminatean ablation. Suction module 61 may comprise a syringe cylinder 62,syringe plunger 63, syringe actuator 64, and a vacuum sensor 60.Alternatively a suction module may comprise a pump with an actuator andvacuum sensor not shown. Foot switch 60 is configured to actuate suctionby switch depression, and deactivate suction upon removal of saiddepression. As shown in FIG. 12, the system may be used in the followingmanner:

Step i 350, the carotid access sheath 1 is inserted into a patient andthe distal end is positioned within the common carotid artery 6. TheETCALS catheter 46 is inserted into the proximal central lumen 124 ofcarotid access sheath 1 and advanced through central lumen 124 until thesuction cup 48 extends beyond the carotid access sheath 1. The suctioncup 48 is maneuvered using visual guidance (e.g., fluoroscopy,sonography) into contact with external carotid artery 17 proximate acarotid body 18.

Step ii 351, the suction cup position is determined to be in a desiredposition or not, if yes proceed to step iii, if not proceed to step i;

Step iii 352, foot switch 65 is depressed activating suction module 61,for example: Syringe actuator 64 is opened resulting in suction, oralternatively vacuum pump is activated;

Step iv 353, vacuum pressure is continuously monitored by vacuum sensor60 to determine if suction is within range or not, if yes proceed tostep v, if not proceed to step i;

Step v 354, when vacuum pressure reaches a predetermined level (e.g.,between 10 mmHg and 100 mmHg) the syringe movement is stopped, oralternatively vacuum pump is stopped, and a cryo-ablation interlock isremoved allowing user actuated cryo-ablation;

Step vi 355, a cryo-ablation or a temporary cryo-block is activated(e.g., cryogen fluid flow is initiated);

Step vii 356, If the vacuum pressure decays to a level below thepredetermined level, then the syringe actuator 64 is again moved toopen, or alternatively the vacuum pumps is activated until thepredetermined vacuum level is re-achieved. If the predetermined levelcannot be achieved initially, or re-achieved within a syringe volumedisplacement between 1 cc and 20 cc then the ablation interlock remainsin activation, or is reactivated, and the blood removed from the patientby the suction module is reinserted back into the patient. Userinterface 68 is configured to provide the user with an indication of thestatus of suction module 61, as well as the status of the cryo-ablationinterlock.

Step viii 357, once the cryo-ablation or temporary cryo-block iscomplete, suction may be continued so position is maintained whiletissue thaws. Maintaining position may allow a repeat cryo-ablation tobe performed in the same location, which may improve efficacy.

The ETCALS catheter 46, and the carotid access sheath 1 are withdrawnfrom the target area.

Control module 66, shown in FIG. 11, may be configured to supplyelectrode(s) mounted in the region of the distal region of ETCALScatheter 46, not shown with neural stimulation energy, and/or neuralblockade energy. The ETCALS catheter 46 may also be configured to workwith a needle device used to access the periarterial space of thecarotid septum 140 for the purposes of applying ablation energy, neuralstimulation energy, neural blockade energy, neural stimulationchemicals, neural blockade chemical, neuro-protective warming, orplacement of a temperature sensor, not shown. The control module 66 maybe configured to supply and control the function of said needledevice(s).

FIG. 13A depicts an Endovascular Transmural Cryo Ablation Balloon(ETCAB) catheter 68 with a balloon not inflated. FIG. 13B depicts theETCAB catheter 68 with the balloon inflated. FIGS. 13C(i)-(iv) depictsectional views A-A, B-B, C-C, and D-D from FIG. 13A. ETCAB catheter 68comprises common catheter shaft 82, cryo catheter shaft 80, guide wireshaft 75 in extension of cryo catheter shaft, distal melt liner 78,balloon shaft 79, cryo-ablation element 72, balloon 69, proximal meltliner 81, and a proximal terminal, not shown. The proximal terminalcomprises a cryogen fluid supply and return connector, an electricalconnector, and a fluid connector for inflation of balloon 69. Commoncatheter shaft 82 comprises balloon inflation lumen 86, electrical wirelumen 83, and cryogen gas return lumen 85. Cryo catheter shaft segment80 comprises electrical wire lumen 83 and cryogen gas return lumen 85.Balloon shaft segment 79 comprises balloon inflation lumen 86.Electrical wire lumen 83 runs from the distal end of cryo shaft segment80 through proximal melt liner 81, common catheter shaft 82, to theelectrical connector of the proximal terminal, not shown. Electricalwire lumen 83 contains wires to connect temperature sensor 73 with theelectrical connector of the proximal terminal. Balloon inflation lumen86 runs from the distal end of balloon shaft 79, through melt liner 81,common catheter shaft 82 to the fluid connector configured for ballooninflation of the proximal terminal, not shown. Distal melt liner 78forms a connection between guide wire shaft segment 75 and balloon shaftsegment 79. Proximal melt liner 81 connects cryo shaft segment 80 andballoon shaft segment 79 to common catheter shaft 82 by thermal bondingtechnique, which preserves the continuity of cryogen gas return lumen85, electrical wire lumen 83, and balloon inflation lumen 86. Commoncatheter shaft 82, distal melt liner 78, cryo shaft segment 80, guidewire shaft segment 75, balloon shaft segment 79, and proximal melt liner81 are fabricated from a thermoplastic material such as Pebax, orpolyurethane. Cryo-ablation element 72 is mounted between cryo shaftsegment 80 and guide wire shaft segment 75 as shown. Cryo-ablationelement 72 comprises cryo ablation element housing 128, optional heatexchanger 129, capillary tube 130, cryo-ablation element bulkhead 132and temperature sensor 73. Cryo-ablation element 72 may be a thin-walledmetallic structure with high thermal conductivity. Heat exchanger 129may be a porous metallic structure with high thermal conductivity and isdisposed within cryo-ablation element housing 128 in an intimate heattransfer relationship. Heat exchanger 129 may be fabricated using asintering process of a metal with high thermal conductivity such ascopper. Capillary tube 130 is configured to meter the flow of cryogenfrom cryogen supply tube 84 into expansion/evaporation chamber 131 at adetermined rate. Capillary tube 130 may be fabricated, for example, froma stainless steel hypodermic tube or polyimide tube. Optionally acapillary tube may be omitted if a cryogen supply tube 84 and exhaustlumen 85 are sized appropriately. Cryogen supply tube 84 may be bondedby adhesive to capillary tube 130 as shown. Cryogen supply tube 84 maybe configured for delivery of a cryogen under high pressure on the orderof 100 psi to 2000 psi (for example N2O may be delivered at a pressurearound 760 psi). Cryogen supply tube 84 may be fabricated from a polymersuch as polyimide, or from a super elastic metal alloy such as Nitinol.Cryogen supply tube 84 is in fluidic communication with cryogen fluidsupply connector of the proximal terminal, not shown. Cryogen gasexhaust lumen 85 is in fluidic communication with cryogen returnconnector of the proximal terminal not shown. Electrical conductor 133connects temperature sensor 73, and optional neural modulationelectrodes, not shown to the electrical connector of the proximalterminal, not shown. Cryo-ablation element 72 may be bonded to thedistal end of cryo catheter shaft segment 80. Guide wire shaft segment75 is bonded to cryo-ablation element bulkhead 132, as shown. Guide wireentry port 74 is distal and in close proximity to cryo-ablation element72, as shown. An example of a method for placing the catheter 68includes advancing a guide wire through a patient's vasculature to thepatient's external carotid artery then advancing the catheter 68 overthe guide wire, that is, the guide wire may pass in to a port at thedistal tip 77, through lumen 76 in the guide wire shaft segment 75 andout of the guide wire entry port 74. In an alternate embodiment, thecryo-ablation element is a balloon configured as an evaporator thatreceives a liquid cryogen, which evaporates and absorbs heat fromadjacent tissue and exits the balloon as a gas. The techniques forconstructing the alternate embodiment described is familiar to thoseskilled in the art of cryo-balloon catheter making, and therefore arenot further elaborated. Balloon 69 is fabricated from an elastomer suchas silicone rubber, and is centrally mounted on balloon shaft segment 79as shown using adhesive. The wall thickness of balloon 69 may be between0.1 mm and 0.4 mm when the balloon is uninflated as depicted in FIG.13A, and may be inflated to a diameter of 4 mm to 10 mm as depicted inFIG. 13B. Alternatively, balloon 69 may be fabricated from anon-elastomeric material such as PET. Radiopaque marker 71 is mountedcentrally on balloon shaft segment 79 as shown. Balloon shaft segment 79is configured to bend in the opposite direction of the bend in cryo andguide wire shaft segments 80 and 75 respectively as shown in FIG. 13B toprovide the user with a substantially unambiguous fluoroscopicindication of the position of cryo-ablation element 72 within a carotidartery using the fluoroscopic spatial relationship between cryo-ablationelement 72 and radiopaque marker 71. The inflation fluid enters balloon69 and is in fluidic communication with balloon inflation lumen 86.Balloon 69 may be configured to contract in the axial direction inreaction to balloon expansion in the radial direction due to ballooninflation. Axial contraction results in balloon shaft 79 buckling anddisplacing radiopaque marker 71 off the centerline of balloon 69 asshown. Radiopaque marker 71 is shown in substantial diametric oppositionto cryo-ablation element 72. The configuration of balloon 69 for axialcontraction and radial expansion may comprise inelastic filaments 240disposed axially within the wall of balloon 69, or inelastic filamentsdisposed axially on the outer surface of balloon 69, or a woven orknitted structure disposed within the wall of balloon 69 or disposed onthe surface of balloon 69. The buckled position of radiopaque marker 71in substantially diametric opposition to cryo-ablation element 72 may befacilitated by embedding at least one flat metallic wire, not shown,within balloon shaft 79 with the flat side of the wire facingcryo-ablation element 72. The flat wire may be a shape memory alloy suchNitinol, that is formed with a bias, which results in the buckling ofballoon shaft 79 in the direction opposite cryo-ablation element 72.

FIG. 14 depicts ETCAB catheter 68 in position for cryo-ablation of acarotid body 18 immediately following an ablation. As depicted,cryo-ablation element 72 is pressed against the wall of the externalcarotid artery 17 and adjacent to carotid body 18 by balloon 69. In thisdepiction, a guide wire is absent. The ablation of carotid body 18 maybe accomplished using ETCAB catheter comprising the steps of:

Determining the position and size of a target ablation zone, for examplean intercarotid septum 140 (see FIGS. 3A and 3B), for example usingfluoroscopy with use of radiocontrast.

Positioning the distal end of ETCAB catheter 68 into the externalcarotid artery 17 associated with carotid body 18 as shown using a guidewire and fluoroscopic imaging using cryo-ablation element 72, andradiopaque marker 71 as references.

Inflating balloon 69 using the fluid connector of the proximal terminal.

Fluoroscopically confirming cryo-ablation element 72 is in a desiredposition for carotid body ablation.

Selecting cryo-ablation parameters.

Initiating the ablation.

Maintaining and monitoring low temperature in the balloon for theduration known to cause irreversible tissue damage in the tissue volumedefined as carotid septum.

Terminating the ablation.

Deflating balloon 69.

Withdrawing ETCAB catheter 69.

FIG. 15A depicts in simplified schematic form an Endovascular TransmuralCryo Ablation (ETCA) catheter 87. FIG. 15B depicts in cross section viewETCA catheter 87. ETCA catheter 87 comprises cryo-ablation element 89,catheter shaft 88, proximal terminal 91, and optional neural modulationelectrodes 90. Proximal terminal 91 comprises electrical connector 93,cryogen supply connector 92, and cryogen gas return connector 105.Alternatively, a cryogen gas return connector may be omitted and cryogengas may be exhausted to atmosphere. Cryo-ablation element 89 comprisescryo cap 95, optional capillary tube 97, and temperature sensor 98. Cryocap 95 may be a thin walled metallic structure with high thermalconductivity. Capillary tube 97 is configured to meter the flow ofcryogen from cryogen supply tube 100 into expansion/evaporation chamber94 at a determined rate. Optionally a capillary tube may be omitted if acryogen supply tube 100 and exhaust lumen 99 are sized appropriately.Capillary tube 97 may be fabricated for example from a stainless steelhypodermic tube or a polymer such as polyimide. Temperature sensor 98may be positioned in expansion chamber 94, for example in contact withan inner wall of the cryo cap 95. Cryogen supply tube 100 may be bondedby adhesive to capillary tube 97 as shown. Cryo-ablation element 89 maybe bonded to the distal end of catheter shaft 87. Catheter shaft 87 maybe fabricated from a polymer such as Pebax or polyurethane, with anouter diameter between 5 French and 12 French. The working length ofcatheter 87 is between 90 cm and 140 cm. Cryogen supply tube 100 isconfigured for delivery of a cryogen under high pressure on the order of100 psi to 2000 psi. Cryogen supply tube 100 may be fabricated from apolymer, or from a superelastic metal alloy such as Nitinol. Cryogensupply tube 100 is in fluidic communication with cryogen connector 92.Exhaust lumen 99 may be in fluidic communication with cryogen gas returnconnector 105 or be exhausted to atmosphere. Electrical cable 134 mayconnect temperature sensor 98, or neural modulation electrodes 90 toelectrical connector 93.

FIG. 16A depicts the distal end of ETCA catheter 87 in workingconfiguration with steerable carotid access sheath 1. FIG. 16B depictsan alternate embodiment of ETCA catheter 102 with steering capabilitycomprising a user deflectable segment 103 and a non-deflectable segment104 proximal to deflectable segment 103. Deflectable segment 103 may beactuated by a pull wire, and a deflection actuator disposed on a handleof proximal terminal, not shown. An ice ball 27 is depicted to representa cryo-ablation functional modality.

FIG. 17 depicts in simplified schematic form an ETCA system. The ETCAsystem comprises ETCA catheter 87, control console 109, cryogen source111, electrical umbilical 106, cryogen umbilical 110, and cryogen supplyline 112. Control console 109 may have a user interface 108 thatprovides the user with a means to select cryo-ablation parameters,activate and deactivate a cryo-ablation, and to monitor the progress ofa cryo-ablation. In addition, control console 109 may have second userinterface 107 that allows the user to select electrical neuro-modulationparameters, activate neuro-modulation, deactivate neuro-modulation, andto monitor neuro-modulation. Control console 109 comprises a means tocontrol the flow of cryogen from cryogen source 111 to ETCA catheter 87according to user settings of user interface 108. Referring to FIG. 15Aand FIG. 15B, an example of operation of an ETCA system may involve thefollowing steps: ETCA ablation element 89 receives cryogen under highpressure from cryogen source 111 via control console 109, cryogenumbilical 110, cryogen connector 92, and cryogen supply tube 100.Cryogen under high pressure enters expansion/evaporation chamber 94where a lower pressure allows the cryogen to change phase from asubstantially liquid state to a substantially gas state resulting in adrop in temperature, which is dependent on the cryogen used, pressureand temperature of the cryogen prior to expansion/evaporation, andexpansion/evaporation pressure. Temperature sensor 98 may be used by thecontrol console 109 to control the flow the cryogen from control console109 to ETCA catheter 87 by means of flow or pressure modulation, or theflow of cryogen gas out of the exhaust lumen 99, which would affect thepressure in the expansion chamber and thus the temperature of cryogen atphase change. Alternatively and optionally temperature sensor 98 may beused to determine that the ETCA system is working properly, or todetermine following cryo-ablation if temperature has risen enough fortissue to thaw and cryo-adhesion to be released. The cryogen exitsexpansion chamber 94 into exhaust lumen 99 and out cryogen return gasconnector 105 or released to atmosphere.

Cryogen may be supplied to cryo-ablation element 89 in the form of afluid that is substantially liquid such liquid nitrogen, liquid carbondioxide, or liquid nitrous oxide resulting in an endothermic phasechange or an evaporative cooling process. Alternatively, a cryogen maybe supplied to cryo-ablation element 89 in the form of a gas such asargon, nitrous oxide, nitrogen, or carbon dioxide where the coolingprocess is by Joule-Thomson effect, which is an adiabatic expansion. Thesurface temperature of cryo-ablation element 89 may be controlled bycontrol console 109 at a temperature between zero degrees centigrade and−120 degrees centigrade during ablation by controlling the flow rate, ortemperature of the cryogen or pressure in the expansion chamber. Thesystem described may also be configured for use with an EndovascularTransmural Cryo Ablation catheter described above, or with aPercutaneous Cryo Ablation Probe described below.

FIG. 18 depicts a steerable configuration of ETCA catheter 102 inposition for ablation of carotid body 18 immediately following anablation with a zone of frozen tissue 40 depicted. As depictedcryo-ablation element 89 has been positioned against a wall of externalcarotid artery 17 proximate to carotid body 18 by a user usingfluoroscopic guidance and the steering capability of ETCA catheter 102comprising deflectable distal segment 103, and non-deflectable segment104. ETCA catheter 102 may also be positioned within the internalcarotid artery 16, and alternately the internal jugular vein 20 fortransmural cryo-ablation of carotid body 18, not shown.

FIG. 19A depicts the use of a steerable ETCA catheter 102 in an internaljugular vein 20 for ablation of carotid body 18. ETCA catheter 102 isinserted into a peripheral vein such as the clavicle vein or femoralvein, not shown, and then navigated into the internal jugular vein withcryo-ablation 89 positioned at the level of the carotid body, as shownusing standard fluoroscopic guidance or other visual guidancetechnology. Alternatively, direct puncture of jugular vein in the neckcan be used to gain access to the desired location near a carotid arterybifurcation. For example, over the wire ultrasound-guided right internaljugular vein access is well known in anesthesiology, hemodynamicmonitoring or endomyocardial biopsy. FIG. 19B depicts the manipulationof the wall of the internal jugular vein with the steering function ofETCA catheter 102 to position cryo-ablation element 89 in closeproximity to carotid body 18. It is noted here that the internal jugularvein 20 is a mobile and elastic structure and may be manipulated by ETCAcatheter 102 to position cryo-ablation element 89 in close proximity tocarotid body 18. FIG. 19C depicts a cryo-ablation of carotid body 18with frozen tissue 40 encompassing carotid body 18. The procedure ofmaneuvering and steering the cryo-ablation element 89 in close proximityto target can be assisted by an external ultrasound that can be multipleplane ultrasound and may have Doppler capability to identify the carotidbifurcation by high velocity of blood stream.

FIG. 20 depicts a Two Zone Percutaneous Cryo Ablation probe (TZPCA) 114.TZPCA probe 114 is configured to cryo-ablate a carotid body bypercutaneous access, and to protect nervous structures from cold injurydistal to the tip of the probe using a distal warming means. Forexample, a distal warming means may protect tissue from cold injury bymaintaining tissue temperature above about 0° C. (e.g., above about 10°C.) and below a temperature that may cause thermal injury (e.g., belowabout 50° C.). TZPCA probe 114 is an elongated structure comprising ashaft 115, a distal region comprising warming element 119, and proximalto warming element 119 cryo-ablation element 121, and a proximalterminal 116, which may comprise cryogen supply connector 117,electrical connector 118, and cryogen return gas connector 135(alternatively, cryogen return gas connector may be omitted and gas maybe exhausted to atmosphere). Shaft 115 may be a rigid metallic structurefabricated from a stainless steel hypo tube or rigid polymer, or may bea hollow flexible structure fabricated from a polymer. Shaft 115 has acaliber suitable for insertion though a percutaneous cannula 14 with anouter diameter between 1 mm and 2 mm, and a length between 5 cm and 15cm long (e.g., between about 8 cm and 10 cm long). As depicted, shaft115 is a stainless steel hypo-tube with a rounded distal tip. Thecryo-ablation element 121 may comprise an expansion/evaporation chamber170, a temperature sensor 122, and a cryogen supply tube 127 incommunication with cryogen supply connector 117 with cryogen gasexhausting the probe through an exhaust lumen 171 which may be connectedto return cryogen gas connector 135 or exhausted to atmosphere. Cryogensupply tube 127 may have exit lumens 172 that allow cryogen to escapethe supply lumen 127 into the expansion chamber 170 directed toward thesides of the inner wall of the cryo-ablation element 121. Warmingelement 119 may be formed by configuring the distal tip as an RF warmingelectrode. A thermally insulative material such as silicone 174 may bepositioned between the cryo-ablation element and the warming element toreduce thermal conduction. The warming element electrode may be formedby coating shaft 115 with an electrically insulative coating 123 (e.g.,PET, or Polyimide) except at the distal tip as shown, and electricallyconnecting shaft 115 to a source of heating that can be RF energy orother source of controllable heat. If RF energy is used to warm tissueproximate the warming element 119 a dispersive electrode may be placedon a patient's skin to complete the RF circuit. In addition, atemperature sensor 120 is mounted in thermal association with theuncoated warming element electrode 119. Shaft 115, cryo-ablationtemperature 122, and warming element temperature sensor 120 areconnected to electrical connector 118 by wires 173 running through achannel of shaft 115 and proximal terminal 116. The distal heatingelement may be configured to heat by alternate energy means includingultrasonic, laser, microwave energy, or by a resistive heating element.

FIG. 21 is a sectional view of a TZPCA probe during a cryo-ablation,where a warming element 119 is protecting sympathetic nerve 23 and othervulnerable structures medial of carotid septum from cold injury bypreventing frozen tissue 40 from expanding in the distal direction. Forexample, frozen tissue 40 may be cooled to a cryo-ablative temperature(e.g., 40° C. or lower) while the warming element may preventcryo-ablative temperature from spreading in a distal direction. Thewarming element may allow tissue distal to the cryo-ablation element toremain in a temperature range that does not cause thermal injury, forexample, above −40° C. (e.g., above −20° C., or above 0° C., or above10° C.) and below about 50° C. (e.g., below about 45° C.).

FIGS. 22A and 22B show a schematic view of a cryo ablation catheter 210having a first deployable arm 211 and a second deployable arm 212 forpositioning along the internal 16 and external 17 carotid artery sidesof an intercarotid septum 140. The arms 211 and 212 carry a cryogenfluid, such as nitrogen, argon, neon, or helium, maintained at nearcritical pressure and temperature. Near critical temperature andpressure is at a temperature and pressure within about 10% of theliquid-vapor critical point, which has a viscosity similar to gas yet adensity and thermal capacity similar to liquid making it a veryefficient coolant. The arms deploy substantially into a V-shape forbifurcation apposition. Arm length 219 allows them to contact both sidesof the intercarotid septum 140 and pull heat from tissue of the septumthus cryogenically ablating the septum. For example, arm length 219 maybe between about 5 mm and 20 mm long (e.g., about 15 mm). Arm length 219is the distance from a location at which the arm initially extends awayfrom the axis of the catheter to a distal end of the arm. At least onearm length 219 can be between about 2.5 mm and about 20 mm. At least onearm length 219 can be between about 2.5 mm and about 15 mm. At least onearm length 219 can be between about 2.5 mm and about 10 mm. At least onearm length 219 can be between about 5 mm and about 15 mm. At least onearm length 219 can be between about 5 mm and about 10 mm. At least onearm length 219 can be between about 10 mm and about 20 mm. At least onearm length 219 can be between about 10 mm and about 15 mm. At least onearm length 219 can be between about 15 mm and about 20 mm. The first arm211 comprises a cryogen delivery tube 213 and a cryogen return tube 214connected at a distal end with an end cap 220. A lumen 222 in deliverytube 213 is in fluid communication through end cap 220 with a lumen 223in return tube 214. The delivery tube 213 and return tube 214 travel alength of catheter 210 to a proximal end terminating in a fluidconnector. Likewise, the second arm 212 has similar components as thefirst arm 211, including a cryogen delivery tube 215 with a lumen 225 influid communication through an end cap 221 with a lumen 224 in a cryogenreturn tube 216. The cryogen delivery and return tubes may be made froma material that maintains flexibility and strength in a range oftemperature from about −200 degrees Celsius to +50 degrees Celsius.Superelastic arms 217 and 218 have a preformed bend 226 and 227 thatcause the arms to deploy into a V-shape when a delivery sheath 1 isretracted. For example, the arms may bend away from an axis of catheter210 at an angle of about 30 to 60 degrees (e.g., about 45 degrees). Thesuperelastic arms 217 and 218 and end caps 220 and 221 may be made fromNitinol and may have a radiopaque coating added to enhance visualizationon fluoroscopy. Near critical cryogen fluid may be supplied to thecatheter 210 by a pump as is known in the art.

FIG. 23 is a cutaway illustration of a lateral view of a patient's rightcarotid artery system with a schematic view of cryo ablation catheter210 delivered through a delivery sheath 1 and positioned at a patient'sintercarotid septum 140. The catheter 210 may be delivered within thesheath 1 to a patient's common carotid artery 6 in a constrained state.Then the sheath 1 may be retracted exposing the arms and bends 226 and227 so the preformed superelastic material causes the arms to deployinto an open V-shape. The arms may be advanced under fluoroscopicguidance into contact with carotid bifurcation 4. Optionally, the sheath1 may be advanced over the bends to close the V-shape of the arms untilthey contact vessel walls of the intercarotid septum. Once in contactcryogen may be delivered through the catheter 210 to cryo ablate theseptum.

A system including a delivery sheath 1 for delivering a balloon catheter230 to the site of a carotid body is shown in FIG. 24. The ballooncatheter comprises a distal balloon 231 and a carotidbifurcation-coupling member 232. The balloon catheter may have a lumen233 through which a cryo-ablation catheter 234 is passed. The balloon231 may be inflated with low pressure in the external carotid artery 17.Then the cryo-ablation catheter 234 may be advanced through the lumen233 into the balloon 231. A deflection means such as an angled hole 235may direct the cryo-ablation catheter 234 towards a side of the balloon.The area where the cryo-ablation element 237 contacts the wall of theballoon may be referred to as the ablation element contact zone 236. Theballoon 231 functions to stabilize the catheter in the vessel and alsoto reduce or stop blood flow around the cryo-ablation element 237, thusreducing a heat sink from the blood and allowing the cryo-ablationelement 237 to create a sufficiently large ablation in a carotid septum140. The balloon may be semi-compliant or non-compliant and besymmetrical, or be asymmetric to bring the shaft and lumen 233 closer tothe ablation site. The balloon catheter may contain radiopaque markersto facilitate visualization and placement. The cryo-ablation catheter234 may contain a controllable deflection means that assists inpositioning the ablation element 237. The balloon 231 may be positionedat a carotid bifurcation 4 such that the proximal end of the balloon ispositioned at the bifurcation and the distal end of the balloon ispositioned about 15 mm beyond the bifurcation. This ensures thecryo-ablation element is positioned an appropriate height from thebifurcation. The ablation element 237 may be free to move anywhere alongthe inner balloon wall, or it may be restricted to contact only a sideof the balloon wall that is facing the bifurcation coupling member 232.The ablation element 237 may be in the range of 3 to 5 French and of alength between 2 and 5 mm. The ablation element may be a material ofhigh thermal conductivity such as copper, nickel, or stainless steel.The cryo-ablation catheter may utilize a cooling technique such asliquid evaporation (e.g., N₂O) or near critical fluid circulation (e.g.,N₂). In either case the balloon catheter 230 and delivery sheath 1 willprovide insulation protection along the length of the catheter shaft.

As shown in FIG. 25, a balloon catheter 245 may be configured to placean occluding balloon 246 distal to a cryo-ablation element 247 in anexternal carotid artery 17 to occlude blood flow and reduce the heatsink tendency of flowing blood to allow the cryo-ablation element 247 tocreate a sufficiently large ablation. In this embodiment thecryo-ablation catheter 248 is advanced through a lumen 249 in theballoon catheter 245 and deployed from the lumen through an exit port250 in the side of the balloon catheter directed toward abifurcation-coupling member 251 at a desired height from the couplingmember (e.g., 4 to 10 mm distal from the coupling member).

The carotid bifurcation coupling member 251 may be an arm with anelastic member having a preformed shape such that when the distal regionof the catheter is advanced out of a delivery sheath 1 the member 251deploys. The preformed shape may comprise a bend so the member deploysat an angle of about 30 to 50 degrees from the catheter shaft. Themember 251 may have a soft, rounded tip 252 to reduce risk of vesseltrauma or plaque dislodgement. Alternatively, a bifurcation couplingmember may be a guidewire passed through a lumen in the catheter and outof a side port near a distal end of the catheter (not shown). Theposition at which the bifurcation coupling member 251 diverges from thecatheter 245 may be about 4 to 20 mm proximal to the exit port 250. Thisarrangement allows a user to advance the catheter 245 from a deliverysheath 1, rotate the catheter to aim the bifurcation coupling member 251at an internal carotid artery 16 and the balloon 246 at an externalcarotid artery 17, then advance the catheter 245 to couple the divergingmember 251 with the carotid bifurcation 4, and the ablation elementcontact zone would be placed at an ideal distance from the carotidbifurcation and rotational position in the artery to target a carotidbody or its associated nerves.

Methods of Therapy:

There may be danger of creating a brain embolism while performing anendovascular procedure in a patient's carotid artery, for example, athrombus may be created by delivering ablation energy, or a piece ofatheromatous plaque may be dislodged by catheter movement. In additionto a carotid body ablation catheter, an endovascular catheter may beused to place a brain embolism protection device in a patient's internalcarotid artery during a carotid body ablation procedure. The treatmentmay include occluding a patient's internal carotid artery. Blood flowingfrom a common carotid artery 59 would not flow through a connectinginternal carotid artery 30, which feeds the brain, but instead wouldflow through the external carotid artery 29, which feeds otherstructures of the head that are much more capable of safely receiving anembolism. For example, a brain embolism protection device in the form ofan inflatable balloon is placed in an internal carotid artery. Theballoon may be made from a soft, stretchable, compliant balloon materialsuch as silicone and may be inflated with a fluid (e.g., saline orcontrast agent) through an inflation lumen. The inflation fluid may beinjected into an inlet port by a syringe or by a computer controlledpump system. The balloon may be placed, using a delivery sheath, in aninternal carotid artery (e.g., up to about 10 cm from a carotidbifurcation). Contrast solution may be injected into the common carotidartery, for example through the delivery sheath to allow radiographicvisualization of the common, internal and external carotid arteries,which may assist a physician to position a brain embolism protectiondevice. An endovascular ablation catheter may place an energy deliveryelement proximate a carotid body, for example at a carotid septum. It isexpected that blood flow would carry any debris into the externalcarotid artery where it is harmless. Occlusion of an internal carotidartery may be done for a period of time that allows an ablationprocedure and that is safe for the brain (e.g., less than or equal toabout 3 minutes, or between about 1 to 2 minutes). After the carotidbody is ablated the brain embolism protection device may be deployed andremoved from the patient or positioned on the patient's contralateralside in the event of ablating the contralateral carotid body.

In another embodiment a brain embolism protection device may be ablood-permeable filter deployed in a patient's internal carotid artery.A filter may be a fine mesh or net connected to a deployable frame thatexpands to envelop a cross-section of an internal carotid artery distalto a bifurcation. Other embodiments of a blood-permeable filter mayinclude wire-type expandable devices such as baskets or umbrellas. Sucha filter may allow antegrade blood flow to continue to the brain whiletrapping and retrieving debris in the blood, preventing a brainembolism. Such a device may be deployed in an internal carotid arteryprior to the placement of ablation catheter and retrieved followingablation.

A cryogen source and optionally a cryo-console may be located externalto the patient. The console may include computer controls toautomatically or manually adjust parameters such as cryogen flow rate,temperature, back pressure, or pressure in an expansion chamber, as wellas timing and period during which cryogenic energy is applied, andsafety limits to the application of energy. A console may also providean indication (e.g., a timer countdown) of cryogenic exposure durationor temperature that may result in temporary nerve blockage, or anindication of cryogenic exposure duration or temperature that may resultin permanent ablation. It should be understood that embodiments ofcryo-devices described herein may be electrically and fluidicallyconnected to the generator even though the generator is not explicitlyshown or described with each embodiment.

An ablated tissue lesion at or near the carotid body may be created bythe application of cryogenic energy from a cryo-element proximate to adistal end of a carotid body ablation device. The ablated tissue lesionmay disable the carotid body or may suppress the activity of the carotidbody or interrupt conduction of afferent nerve signals from a carotidbody to sympathetic nervous system. The disabling or suppression of thecarotid body reduces the responsiveness of the glomus cells to changesof blood gas composition and effectively reduces activity of afferentcarotid body nerves or the chemoreflex gain of the patient.

A method in accordance with a particular embodiment includes ablating atleast one of a patient's carotid bodies based at least in part onidentifying the patient as having a sympathetically mediated diseasesuch as cardiac, metabolic, or pulmonary disease such as hypertension,insulin resistance, diabetes, pulmonary hypertension, drug resistanthypertension (e.g., refractory hypertension), congestive heart failure(CHF), or dyspnea from heart failure or pulmonary disease causes.

A procedure may include diagnosis, selection based on diagnosis, furtherscreening (e.g., baseline assessment of chemosensitivity), treating apatient based at least in part on diagnosis or further screening via achemoreceptor (e.g., carotid body) ablation procedure such as one of theembodiments disclosed. Additionally, following ablation a method oftherapy may involve conducting a post-ablation assessment to comparewith the baseline assessment and making decisions based on theassessment (e.g., adjustment of drug therapy, re-treat in new positionor with different parameters, or ablate a second chemoreceptor if onlyone was previously ablated).

A carotid body ablation procedure may comprise the following steps or acombination thereof: patient sedation, locating a target peripheralchemoreceptor, visualizing a target peripheral chemoreceptor (e.g.,carotid body), confirming a target ablation site is or is proximate aperipheral chemoreceptor, confirming a target ablation site is safelydistant from vital structures that are preferably protected (e.g.,hypoglossal and vagus nerves), providing stimulation (e.g., electrical,mechanical, chemical) to a target site or target peripheralchemoreceptor prior to, during or following an ablation step, monitoringphysiological responses to said stimulation, providing temporarycryogenic nerve block to a target site prior to an ablation step,monitoring physiological responses to said temporary nerve block,anesthetizing a target site, protecting the brain from potentialembolism, thermally protecting an arterial or venous wall (e.g., carotidartery, jugular vein) or a medial aspect of an intercarotid septum orvital nerve structures, cryo-ablating a target site or peripheralchemoreceptor, monitoring ablation parameters (e.g., temperature,pressure, duration, blood flow in a carotid artery), monitoringphysiological responses during ablation and arresting ablation if unsafeor unwanted physiological responses occur before collateral nerve injurybecomes permanent, confirming a reduction of chemoreceptor activity(e.g., chemosensitivity, HR, blood pressure, ventilation, sympatheticnerve activity) during or following an ablation step, removing acryo-ablation device, conducting a post-ablation assessment, repeatingany steps of the chemoreceptor ablation procedure on another peripheralchemoreceptor in the patient.

Patient screening, as well as post-ablation assessment may includephysiological tests or gathering of information, for example,chemoreflex sensitivity, central sympathetic nerve activity, heart rate,heart rate variability, blood pressure, ventilation, production ofhormones, peripheral vascular resistance, blood pH, blood PCO₂, degreeof hyperventilation, peak VO₂, VE/VCO₂ slope. Directly measured maximumoxygen uptake (more correctly pVO₂ in heart failure patients) and indexof respiratory efficiency VE/VCO₂ slope has been shown to be areproducible marker of exercise tolerance in heart failure and provideobjective and additional information regarding a patient's clinicalstatus and prognosis.

A method of therapy may include electrical stimulation of a targetregion, using a stimulation electrode, to confirm proximity to a carotidbody. For example, a stimulation signal having a 1-10 milliamps (mA)pulse train at about 20 to 40Hz with a pulse duration of 50 to 500microseconds (μs) that produces a positive carotid body stimulationeffect may indicate that the stimulation electrode is within sufficientproximity to the carotid body or nerves of the carotid body toeffectively ablate it. A positive carotid body stimulation effect couldbe increased blood pressure, heart rate, or ventilation concomitant withapplication of the stimulation. These variables could be monitored,recorded, or displayed to help assess confirmation of proximity to acarotid body. A catheter-based technique, for example, may have astimulation electrode proximal to the cryo-element used for ablation.Alternatively, the cryo-element itself may also be used as a stimulationelectrode. Alternatively, a cryogenic ablation applicator may beconfigured to also deliver an electrical stimulation signal as describedearlier. Yet another alternative embodiment comprises a stimulationelectrode that is distinct from an ablation element. For example, duringa surgical procedure a stimulation probe can be touched to a suspectedcarotid body that is surgically exposed. A positive carotid bodystimulation effect could confirm that the suspected structure is acarotid body and ablation can commence. Physiological monitors (e.g.,heart rate monitor, blood pressure monitor, blood flow monitor, MSNAmonitor) may communicate with a computerized stimulation generator,which may also be an ablation generator, to provide feedback informationin response to stimulation. If a physiological response correlates to agiven stimulation the computerized generator may provide an indicationof a positive confirmation.

Alternatively or in addition a drug known to excite the chemo sensitivecells of the carotid body can be injected directly into the carotidartery or given systemically into a patient's vein or artery in order toelicit hemodynamic or respiratory response. Examples of drugs that mayexcite a chemoreceptor include nicotine, atropine, Doxapram, Almitrine,hyperkalemia, Theophylline, adenosine, sulfides, Lobeline,Acetylcholine, ammonium chloride, methylamine, potassium chloride,anabasine, coniine, cytosine, acetaldehyde, acetyl ester and the ethylether of i-methylcholine, Succinylcholine, Piperidine, monophenol esterof homo-iso-muscarine and acetylsalicylamides, alkaloids of veratrum,sodium citrate, adenosinetriphosphate, dinitrophenol, caffeine,theobromine, ethyl alcohol, ether, chloroform, phenyldiguanide,sparteine, coramine (nikethamide), metrazol (pentylenetetrazol),iodomethylate of dimethylaminomethylenedioxypropane,ethyltrimethylammoniumpropane, trimethylammonium, hydroxytryptamine,papaverine, neostigmine, acidity.

A method of therapy may further comprise applying electrical or chemicalstimulation to the target area or systemically following ablation toconfirm a successful ablation. Heart rate, blood pressure or ventilationmay be monitored for change or compared to the reaction to stimulationprior to ablation to assess if the targeted carotid body was ablated.Post-ablation stimulation may be done with the same apparatus used toconduct the pre-ablation stimulation. Physiological monitors (e.g.,heart rate monitor, blood pressure monitor, blood flow monitor, MSNAmonitor) may communicate with a computerized stimulation generator,which may also be an ablation generator, to provide feedback informationin response to stimulation. If a physiological response correlated to agiven stimulation is reduced following an ablation compared to aphysiological response prior to the ablation, the computerized generatormay provide an indication ablation efficacy or possible proceduralsuggestions such as repeating an ablation, adjusting ablationparameters, changing position, ablating another carotid body orchemosensor, or concluding the procedure.

Visualization:

An optional step of visualizing internal structures (e.g., carotid bodyor surrounding structures) may be accomplished using one or morenon-invasive imaging modalities, for example fluoroscopy, radiography,arteriography, computer tomography (CT), computer tomography angiographywith contrast (CTA), magnetic resonance imaging (MRI), or sonography, orminimally invasive techniques (e.g., IVUS, endoscopy, optical coherencetomography, ICE). A visualization step may be performed as part of apatient assessment, prior to an ablation procedure to assess risks andlocation of anatomical structures, during an ablation procedure to helpguide an ablation device, or following an ablation procedure to assessoutcome (e.g., efficacy of the ablation). Visualization may be used to:(a) locate a carotid body, (b) locate vital structures that may beadversely affected, or (c) locate, identify and measure arterial plaque.

Endovascular (for example transfemoral) arteriography of the commoncarotid and then selective arteriography of the internal and externalcarotids may be used to determine a position of a catheter tip at acarotid bifurcation. Additionally, ostia of glomic arteries (thesearteries may be up to 4 mm long and arise directly from the main parentartery) can be identified by dragging the dye injection catheter andreleasing small amounts (“puffs”) of dye. If a glomic artery isidentified it can be cannulated by a guide wire and possibly furthercannulated by small caliber catheter. Direct injection of dye intoglomic arteries can further assist the interventionalist in the ablationprocedure. It is appreciated that the feeding glomic arteries are smalland microcatheters may be needed to cannulate them.

Alternatively, ultrasound visualization may allow a physician to see thecarotid arteries and even the carotid body. Another method forvisualization may consist of inserting a small needle (e.g., 22 Gauge)with sonography or computer tomography (CT) guidance into or toward thecarotid body. A wire or needle can be left in place as a fiducial guide,or contrast can be injected into the carotid body. Runoff of contrast tothe jugular vein may confirm that the target is achieved.

Computer Tomography (CT) and computer tomography angiography (CTA) mayalso be used to aid in identifying a carotid body. Such imaging could beused to help guide an ablation device to a carotid body.

Ultrasound visualization (e.g., sonography) is an ultrasound-basedimaging technique used for visualizing subcutaneous body structuresincluding blood vessels and surrounding tissues. Doppler ultrasound usesreflected ultrasound waves to identify and display blood flow through avessel. Operators typically use a hand-held transducer/transceiverplaced directly on a patient's skin and aimed inward directingultrasound waves through the patient's tissue. Ultrasound may be used tovisualize a patient's carotid body to help guide an ablation device.Ultrasound can be also used to identify atherosclerotic plaque in thecarotid arteries and avoid disturbing and dislodging such plaque.

Visualization and navigation steps may comprise multiple imagingmodalities (e.g., CT, fluoroscopy, ultrasound) superimposed digitally touse as a map for instrument positioning. Superimposing borders of greatvessels such as carotid arteries can be done to combine images.

Responses to stimulation at different coordinate points can be storeddigitally as a 3-dimensional or 2-dimenisional orthogonal plane map.Such an electric map of the carotid bifurcation showing points, or pointcoordinates that are electrically excitable such as baroreceptors,baroreceptor nerves, chemoreceptors and chemoreceptor nerves can besuperimposed with an image (e.g., CT, fluoroscopy, ultrasound) ofvessels. This can be used to guide the procedure, and identify targetareas and areas to avoid.

In addition, as noted above, it should be understood that a deviceproviding therapy can also be used to locate a carotid body as well asto provide various stimuli (electrical, chemical, other) to test abaseline response of the carotid body chemoreflex (CBC) or carotid sinusbaroreflex (CSB) and measure changes in these responses after therapy ora need for additional therapy to achieve the desired physiological andclinical effects.

Patient Selection and Assessment:

In an embodiment, a procedure may comprise assessing a patient to be aplausible candidate for carotid body ablation. Such assessment mayinvolve diagnosing a patient with a sympathetically mediated disease(e.g., MSNA microneurography, measure of cataclomines in blood or urine,heart rate, or low/high frequency analysis of heart rate variability maybe used to assess sympathetic tone). Patient assessment may furthercomprise other patient selection criteria, for example indices of highcarotid body activity (i.e., carotid body hypersensitivity orhyperactivity) such as a combination of hyperventilation and hypocarbiaat rest, high carotid body nerve activity (e.g., measured directly),incidence of periodic breathing, dyspnea, central sleep apnea elevatedbrain natriuretic peptide, low exercise capacity, having cardiacresynchronization therapy, atrial fibrillation, ejection fraction of theleft ventricle, using beta blockers or ACE inhibitors.

Patient assessment may further involve selecting patients with highperipheral chemosensitivity (e.g., a respiratory response to hypoxianormalized to the desaturation of oxygen greater than or equal to about0.7 l/min/min SpO₂), which may involve characterizing a patient'schemoreceptor sensitivity, reaction to temporarily blocking carotid bodychemoreflex, or a combination thereof.

Although there are many ways to measure chemosensitivity they can bedivided into (a) active provoked response and (b) passive monitoring.Active tests can be done by inducing intermittent hypoxia (such as bytaking breaths of nitrogen or CO₂ or combination of gases) or byrebreathing air into and from a 4 to 10 liter bag. For example: ahypersensitive response to a short period of hypoxia measured byincrease of respiration or heart rate may provide an indication fortherapy. Ablation or significant reduction of such response could beindicative of a successful procedure. Also, electrical stimulation,drugs and chemicals (e.g., dopamine, lidocane) exist that can block orexcite a carotid body when applied locally or intravenously.

The location and baseline function of the desired area of therapy(including the carotid and aortic chemoreceptors and baroreceptors andcorresponding nerves) may be determined prior to therapy by applicationof stimuli to the carotid body or other organs that would result in anexpected change in a physiological or clinical event such as an increaseor decrease in SNS activity, heart rate or blood pressure. These stimulimay also be applied after the therapy to determine the effect of thetherapy or to indicate the need for repeated application of therapy toachieve the desired physiological or clinical effect(s). The stimuli canbe either electrical or chemical in nature and can be delivered via thesame or another catheter or can be delivered separately (such asinjection of a substance through a peripheral IV to affect the CBC thatwould be expected to cause a predicted physiological or clinicaleffect).

A baseline stimulation test may be performed to select patients that maybenefit from a carotid body ablation procedure. For example, patientswith a high peripheral chemosensitivity gain (e.g., greater than orequal to about two standard deviations above an age matched generalpopulation chemosensitivity, or alternatively above a thresholdperipheral chemosensitivity to hypoxia of 0.5 or 0.7 ml/min/% O2) may beselected for a carotid body ablation procedure. A prospective patientsuffering from a cardiac, metabolic, or pulmonary disease (e.g.,hypertension, CHF, diabetes) may be selected. The patient may then betested to assess a baseline peripheral chemoreceptor sensitivity (e.g.,minute ventilation, tidal volume, ventilator rate, heart rate, or otherresponse to hypoxic or hypercapnic stimulus). Baseline peripheralchemosensitivity may be assessed using tests known in the art whichinvolve inhalation of a gas mixture having reduced O₂ content (e.g.,pure nitrogen, CO₂, helium, or breathable gas mixture with reducedamounts of O₂ and increased amounts of CO₂) or rebreathing of gas into abag. Concurrently, the patient's minute ventilation or initialsympathetically mediated physiologic parameter such as minuteventilation or HR may be measured and compared to the O₂ level in thegas mixture. Tests like this may elucidate indices called chemoreceptorsetpoint and gain. These indices are indicative of chemoreceptorsensitivity. If the patient's chemosensitivity is not assessed to behigh (e.g., less than about two standard deviations of an age matchedgeneral population chemosensitivity, or other relevant numericthreshold) then the patient may not be a suitable candidate for acarotid body ablation procedure. Conversely, a patient withchemoreceptor hypersensitivity (e.g., greater than or equal to about twostandard deviations above normal) may proceed to have a carotid bodyablation procedure. Following a carotid body ablation procedure thepatient's chemosensitivity may optionally be tested again and comparedto the results of the baseline test. The second test or the comparisonof the second test to the baseline test may provide an indication oftreatment success or suggest further intervention such as possibleadjustment of drug therapy, repeating the carotid body ablationprocedure with adjusted parameters or location, or performing anothercarotid body ablation procedure on a second carotid body if the firstprocedure only targeted one carotid body. It may be expected that apatient having chemoreceptor hypersensitivity or hyperactivity mayreturn to about a normal sensitivity or activity following a successfulcarotid body ablation procedure.

In an alternative protocol for selecting a patient for a carotid bodyablation, patients with high peripheral chemosensitivity or carotid bodyactivity (e.g., ≥about 2 standard deviations above normal) alone or incombination with other clinical and physiologic parameters may beparticularly good candidates for carotid body ablation therapy if theyfurther respond positively to temporary blocking of carotid bodyactivity. A prospective patient suffering from a cardiac, metabolic, orpulmonary disease may be selected to be tested to assess the baselineperipheral chemoreceptor sensitivity. A patient without highchemosensitivity may not be a plausible candidate for a carotid bodyablation procedure. A patient with a high chemosensitivity may be givena further assessment that temporarily blocks a carotid body chemoreflex.For example a temporary block may be done chemically, for example usinga chemical such as intravascular dopamine or dopamine-like substances,intravascular alpha-2 adrenergic agonists, oxygen, in generalalkalinity, or local or topical application of atropine externally tothe carotid body. A patient having a negative response to the temporarycarotid body block test (e.g., sympathetic activity index such asrespiration, HR, heart rate variability, MSNA, vasculature resistance,etc. is not significantly altered) may be a less plausible candidate fora carotid body ablation procedure. Conversely, a patient with a positiveresponse to the temporary carotid body block test (e.g., respiration orindex of sympathetic activity is altered significantly) may be a moreplausible candidate for a carotid body ablation procedure.

There are a number of potential ways to conduct a temporary carotid bodyblock test. Hyperoxia (e.g., higher than normal levels of PO₂) forexample, is known to partially block (about a 50%) or reduce afferentsympathetic response of the carotid body. Thus, if a patient'ssympathetic activity indexes (e.g., respiration, HR, HRV, MSNA) arereduced by hyperoxia (e.g., inhalation of higher than normal levels ofO₂) for 3-5 minutes, the patient may be a particularly plausiblecandidate for carotid body ablation therapy. A sympathetic response tohyperoxia may be achieved by monitoring minute ventilation (e.g.,reduction of more than 20-30% may indicate that a patient has carotidbody hyperactivity). To evoke a carotid body response, or compare it tocarotid body response in normoxic conditions, CO₂ above 3-4% may bemixed into the gas inspired by the patient (nitrogen content will bereduced) or another pharmacological agent can be used to invoke acarotid body response to a change of CO₂, pH or glucose concentration.Alternatively, “withdrawal of hypoxic drive” to rest state respirationin response to breathing a high concentration O₂ gas mix may be used fora simpler test.

An alternative temporary carotid body block test involves administeringa sub-anesthetic amount of anesthetic gas halothane, which is known totemporarily suppress carotid body activity. Furthermore, there areinjectable substances such as dopamine that are known to reversiblyinhibit the carotid body. However, any substance, whether inhaled,injected or delivered by another manner to the carotid body that affectscarotid body function in the desired fashion may be used.

Another alternative temporary carotid body block test involvesapplication of cryogenic energy to a carotid body (i.e., removal ofheat). For example, a carotid body or its nerves may be cooled to atemperature range between about −15° C. to 0° C. to temporarily reducenerve activity or blood flow to and from a carotid body thus reducing orinhibiting carotid body activity.

An alternative method of assessing a temporary carotid body block testmay involve measuring pulse pressure. Noninvasive pulse pressure devicessuch as Nexfin (made by BMEYE, based in Amsterdam, The Netherlands) canbe used to track beat-to-beat changes in peripheral vascular resistance.Patients with hypertension or CHF may be sensitive to temporary carotidbody blocking with oxygen or injection of a blocking drug. Theperipheral vascular resistance of such patients may be expected toreduce substantially in response to carotid body blocking. Such patientsmay be good candidates for carotid body ablation therapy.

Yet another index that may be used to assess if a patient may be a goodcandidate for carotid body ablation therapy is increase of baroreflex,or baroreceptor sensitivity, in response to carotid body blocking. It isknown that hyperactive chemosensitivity suppresses baroreflex. Ifcarotid body activity is temporarily reduced the carotid sinusbaroreflex (baroreflex sensitivity (BRS) or baroreflex gain) may beexpected to increase. Baroreflex contributes a beneficialparasympathetic component to autonomic drive. Depressed BRS is oftenassociated with an increased incidence of death and malignantventricular arrhythmias. Baroreflex is measurable using standardnon-invasive methods. One example is spectral analysis of RR interval ofECG and systolic blood pressure variability in both the high- andlow-frequency bands. An increase of baroreflex gain in response totemporary blockade of carotid body can be a good indication forpermanent therapy. Baroreflex sensitivity can also be measured by heartrate response to a transient rise in blood pressure induced by injectionof phenylephrine.

An alternative method involves using an index of glucose tolerance toselect patients and determine the results of carotid body blocking orremoval in diabetic patients. There is evidence that carotid bodyhyperactivity contributes to progression and severity of metabolicdisease.

In general, a beneficial response can be seen as an increase ofparasympathetic or decrease of sympathetic tone in the overall autonomicbalance. For example, Power Spectral Density (PSD) curves of respirationor HR can be calculated using nonparametric Fast Fourier Transformalgorithm (FFT). FFT parameters can be set to 256-64 k buffer size,Hamming window, 50% overlap, 0 to 0.5 or 0.1 to 1.0 Hz range. HR andrespiratory signals can be analyzed for the same periods of timecorresponding to (1) normal unblocked carotid body breathing and (2)breathing with blocked carotid body.

Power can be calculated for three bands: the very low frequency (VLF)between 0 and 0.04 Hz, the low frequency band (LF) between 0.04-0.15 Hzand the high frequency band (HF) between 0.15-0.4 Hz. Cumulativespectral power in LF and HF bands may also be calculated; normalized tototal power between 0.04 and 0.4 Hz (TF=HF+LF) and expressed as % oftotal. Natural breathing rate of CHF patient, for example, can be ratherhigh, in the 0.3-0.4 Hz range.

The VLF band may be assumed to reflect periodic breathing frequency(typically 0.016 Hz) that can be present in CHF patients. It can beexcluded from the HF/LF power ratio calculations.

The powers of the LF and HF oscillations characterizing heart ratevariability (HRV) appear to reflect, in their reciprocal relationship,changes in the state of the sympathovagal (sympathetic toparasympathetic) balance occurring during numerous physiological andpathophysiological conditions. Thus, increase of HF contribution inparticular can be considered a positive response to carotid bodyblocking.

Another alternative method of assessing carotid body activity comprisesnuclear medicine scanning, for example with ocretide, somatostatinanalogues, or other substances produced or bound by the carotid body.

Furthermore, artificially increasing blood flow may reduce carotid bodyactivation. Conversely artificially reducing blood flow may stimulatecarotid body activation. This may be achieved with drugs known in theart to alter blood flow.

There is a considerable amount of scientific evidence to demonstratethat hypertrophy of a carotid body often accompanies disease. Ahypertrophied (i.e., enlarged) carotid body may further contribute tothe disease. Thus identification of patients with enlarged carotidbodies may be instrumental in determining candidates for therapy.Imaging of a carotid body may be accomplished by angiography performedwith radiographic, computer tomography, or magnetic resonance imaging.

It should be understood that the available measurements are not limitedto those described above. It may be possible to use any single or acombination of measurements that reflect any clinical or physiologicalparameter effected or changed by either increases or decreases incarotid body function to evaluate the baseline state, or change instate, of a patient's chemosensitivity.

There is a considerable amount of scientific evidence to demonstratethat hypertrophy of a carotid body often accompanies disease. Ahypertrophied or enlarged carotid body may further contribute to thedisease. Thus identification of patients with enlarged carotid bodiesmay be instrumental in determining candidates for therapy.

Further, it is possible that although patients do not meet a preselectedclinical or physiological definition of high peripheral chemosensitivity(e.g., greater than or equal to about two standard deviations abovenormal), administration of a substance that suppresses peripheralchemosensitivity may be an alternative method of identifying a patientwho is a candidate for the proposed therapy. These patients may have adifferent physiology or co-morbid disease state that, in concert with ahigher than normal peripheral chemosensitivity (e.g., greater than orequal to normal and less than or equal to about 2 standard deviationsabove normal), may still allow the patient to benefit from carotid bodyablation. The proposed therapy may be at least in part based on anobjective that carotid body ablation will result in a clinicallysignificant or clinically beneficial change in the patient'sphysiological or clinical course. It is reasonable to believe that ifthe desired clinical or physiological changes occur even in the absenceof meeting the predefined screening criteria, then therapy could beperformed.

Cryogenic ablation of a peripheral chemoreceptor (e.g., carotid body oraortic body) via an endovascular approach in patients havingsympathetically mediated disease and augmented chemoreflex (e.g., highafferent nerve signaling from a carotid body to the central nervoussystem as in some cases indicated by high peripheral chemosensitivity)has been conceived to reduce peripheral chemosensitivity and reduceafferent signaling from peripheral chemoreceptors to the central nervoussystem. The expected reduction of chemoreflex activity and sensitivityto hypoxia and other stimuli such as blood flow, blood CO₂, glucoseconcentration or blood pH can directly reduce afferent signals fromchemoreceptors and produce at least one beneficial effect such as thereduction of central sympathetic activation, reduction of the sensationof breathlessness (dyspnea), vasodilation, increase of exercisecapacity, reduction of blood pressure, reduction of sodium and waterretention, redistribution of blood volume to skeletal muscle, reductionof insulin resistance, reduction of hyperventilation, reduction oftachypnea, reduction of hypocapnia, increase of baroreflex andbarosensitivity of baroreceptors, increase of vagal tone, or improvesymptoms of a sympathetically mediated disease and may ultimately slowdown the disease progression and extend life. It is understood that asympathetically mediated disease that may be treated with carotid bodyablation may comprise elevated sympathetic tone, an elevatedsympathetic/parasympathetic activity ratio, autonomic imbalanceprimarily attributable to central sympathetic tone being abnormally orundesirably high, or heightened sympathetic tone at least partiallyattributable to afferent excitation traceable to hypersensitivity orhyperactivity of a peripheral chemoreceptor (e.g., carotid body). Insome important clinical cases where baseline hypocapnia or tachypnea ispresent, reduction of hyperventilation and breathing rate may beexpected. It is understood that hyperventilation in the context hereinmeans respiration in excess of metabolic needs on the individual thatgenerally leads to slight but significant hypocapnea (blood CO₂ partialpressure below normal of approximately 40 mmHg, for example in the rangeof 33 to 38 mmHg).

Patients having CHF or hypertension concurrent with heightenedperipheral chemoreflex activity and sensitivity often react as if theirsystem was hypercapnic even if it is not. The reaction is tohyperventilate, a maladaptive attempt to rid the system of CO₂, thusovercompensating and creating a hypocapnic and alkalotic system. Someresearchers attribute this hypersensitivity/hyperactivity of the carotidbody to the direct effect of catecholamines, hormones circulating inexcessive quantities in the blood stream of CHF patients. The proceduremay be particularly useful to treat such patients who are hypocapnic andpossibly alkalotic resulting from high tonic output from carotid bodies.Such patients are particularly predisposed to periodic breathing andcentral apnea hypopnea type events that cause arousal, disrupt sleep,cause intermittent hypoxia and are by themselves detrimental anddifficult to treat.

It is appreciated that periodic breathing of Cheyne Stokes patternoccurs in patients during sleep, exercise and even at rest as acombination of central hypersensitivity to CO₂, peripheralchemosensitivity to O₂ and CO₂ and prolonged circulatory delay. Allthese parameters are often present in CHF patients that are at high riskof death. Thus, patients with hypocapnea, CHF, high chemosensitivity andprolonged circulatory delay, and specifically ones that exhibit periodicbreathing at rest or during exercise or induced by hypoxia are likelybeneficiaries of the proposed therapy.

Hyperventilation is defined as breathing in excess of a person'smetabolic need at a given time and level of activity. Hyperventilationis more specifically defined as minute ventilation in excess of thatneeded to remove CO₂ from blood in order to maintain blood CO₂ in thenormal range (e.g., around 40 mmHg partial pressure). For example,patients with arterial blood PCO₂ in the range of 32-37 mmHg can beconsidered hypocapnic and in hyperventilation.

For the purpose of this disclosure hyperventilation is equivalent toabnormally low levels of carbon dioxide in the blood (e.g., hypocapnia,hypocapnea, or hypocarbia) caused by overbreathing. Hyperventilation isthe opposite of hypoventilation (e.g., underventilation) that oftenoccurs in patients with lung disease and results in high levels ofcarbon dioxide in the blood (e.g., hypercapnia or hypercarbia).

A low partial pressure of carbon dioxide in the blood causes alkalosis,because CO₂ is acidic in solution and reduced CO₂ makes blood pH morebasic, leading to lowered plasma calcium ions and nerve and muscleexcitability. This condition is undesirable in cardiac patients since itcan increase probability of cardiac arrhythmias.

Alkalemia may be defined as abnormal alkalinity, or increased pH of theblood. Respiratory alkalosis is a state due to excess loss of carbondioxide from the body, usually as a result of hyperventilation.Compensated alkalosis is a form in which compensatory mechanisms havereturned the pH toward normal. For example, compensation can be achievedby increased excretion of bicarbonate by the kidneys.

Compensated alkalosis at rest can become uncompensated during exerciseor as a result of other changes of metabolic balance. Thus the inventedmethod is applicable to treatment of both uncompensated and compensatedrespiratory alkalosis.

Tachypnea means rapid breathing. For the purpose of this disclosure abreathing rate of about 6 to 16 breaths per minute at rest is considerednormal but there is a known benefit to lower rate of breathing incardiac patients. Reduction of tachypnea can be expected to reducerespiratory dead space, increase breathing efficiency, and increaseparasympathetic tone.

Therapy Example: Role of Chemoreflex and Central Sympathetic NerveActivity in CHF

Chronic elevation in sympathetic nerve activity (SNA) is associated withthe development and progression of certain types of hypertension andcontributes to the progression of congestive heart failure (CHF). It isalso known that sympathetic excitatory cardiac, somatic, andcentral/peripheral chemoreceptor reflexes are abnormally enhanced in CHFand hypertension (Ponikowski, 2011 and Giannoni, 2008 and 2009).

Arterial chemoreceptors serve an important regulatory role in thecontrol of alveolar ventilation. They also exert a powerful influence oncardiovascular function.

Delivery of Oxygen (O₂) and removal of Carbon Dioxide (CO₂) in the humanbody is regulated by two control systems, behavioral control andmetabolic control. The metabolic ventilatory control system drives ourbreathing at rest and ensures optimal cellular homeostasis with respectto pH, partial pressure of carbon dioxide (PCO₂), and partial pressureof oxygen (PO₂). Metabolic control uses two sets of chemoreceptors thatprovide a fine-tuning function: the central chemoreceptors located inthe ventral medulla of the brain and the peripheral chemoreceptors suchas the aortic chemoreceptors and the carotid body chemoreceptors. Thecarotid body, a small, ovoid-shaped (often described as a grain ofrice), and highly vascularized organ is situated in or near the carotidbifurcation, where the common carotid artery branches in to an internalcarotid artery (IC) and external carotid artery (EC). The centralchemoreceptors are sensitive to hypercapnia (high PCO₂), and theperipheral chemoreceptors are sensitive to hypercapnia and hypoxia (lowblood PO₂). Under normal conditions activation of the sensors by theirrespective stimuli results in quick ventilatory responses aimed at therestoration of cellular homeostasis.

As early as 1868, Pflüger recognized that hypoxia stimulatedventilation, which spurred a search for the location of oxygen-sensitivereceptors both within the brain and at various sites in the peripheralcirculation. When Corneille Heymans and his colleagues observed thatventilation increased when the oxygen content of the blood flowingthrough the bifurcation of the common carotid artery was reduced(winning him the Nobel Prize in 1938), the search for the oxygenchemosensor responsible for the ventilatory response to hypoxia waslargely considered accomplished.

The persistence of stimulatory effects of hypoxia in the absence (aftersurgical removal) of the carotid chemoreceptors (e.g., the carotidbodies) led other investigators, among them Julius Comroe, to ascribehypoxic chemosensitivity to other sites, including both peripheral sites(e.g., aortic bodies) and central brain sites (e.g., hypothalamus, ponsand rostral ventrolateral medulla). The aortic chemoreceptor, located inthe aortic body, may also be an important chemoreceptor in humans withsignificant influence on vascular tone and cardiac function.

Carotid Body Chemoreflex:

The carotid body is a small cluster of chemoreceptors (also known asglomus cells) and supporting cells located near, and in most casesdirectly at, the medial side of the bifurcation (fork) of the carotidartery, which runs along both sides of the throat.

These organs act as sensors detecting different chemical stimuli fromarterial blood and triggering an action potential in the afferent fibersthat communicate this information to the Central Nervous System (CNS).In response, the CNS activates reflexes that control heart rate (HR),renal function and peripheral blood circulation to maintain the desiredhomeostasis of blood gases, O₂ and CO₂, and blood pH. This closed loopcontrol function that involves blood gas chemoreceptors is known as thecarotid body chemoreflex (CBC). The carotid body chemoreflex isintegrated in the CNS with the carotid sinus baroreflex (CSB) thatmaintains arterial blood pressure. In a healthy organism these tworeflexes maintain blood pressure and blood gases within a narrowphysiologic range. Chemosensors and barosensors in the aortic archcontribute redundancy and fine-tuning function to the closed loopchemoreflex and baroreflex. In addition to sensing blood gasses, thecarotid body is now understood to be sensitive to blood flow andvelocity, blood Ph and glucose concentration. Thus it is understood thatin conditions such as hypertension, CHF, insulin resistance, diabetesand other metabolic derangements afferent signaling of carotid bodynerves may be elevated. Carotid body hyperactivity may be present evenin the absence of detectable hypersensitivity to hypoxia and hypercapniathat are traditionally used to index carotid body function. The purposeof the proposed therapy is therefore to remove or reduce afferent neuralsignals from a carotid body and reduce carotid body contribution tocentral sympathetic tone.

The carotid sinus baroreflex is accomplished by negative feedbacksystems incorporating pressure sensors (e.g., baroreceptors) that sensethe arterial pressure. Baroreceptors also exist in other places, such asthe aorta and coronary arteries. Important arterial baroreceptors arelocated in the carotid sinus, a slight dilatation of the internalcarotid artery 201 at its origin from the common carotid. The carotidsinus baroreceptors are close to but anatomically separate from thecarotid body. Baroreceptors respond to stretching of the arterial walland communicate blood pressure information to CNS. Baroreceptors aredistributed in the arterial walls of the carotid sinus while thechemoreceptors (glomus cells) are clustered inside the carotid body.This makes the selective reduction of chemoreflex described in thisapplication possible while substantially sparing the baroreflex.

The carotid body exhibits great sensitivity to hypoxia (low thresholdand high gain). In chronic Congestive Heart Failure (CHF), thesympathetic nervous system activation that is directed to attenuatesystemic hypoperfusion at the initial phases of CHF may ultimatelyexacerbate the progression of cardiac dysfunction that subsequentlyincreases the extra-cardiac abnormalities, a positive feedback cycle ofprogressive deterioration, a vicious cycle with ominous consequences. Itwas thought that much of the increase in the sympathetic nerve activity(SNA) in CHF was based on an increase of sympathetic flow at a level ofthe CNS and on the depression of arterial baroreflex function. In thepast several years, it has been demonstrated that an increase in theactivity and sensitivity of peripheral chemoreceptors (heightenedchemoreflex function) also plays an important role in the enhanced SNAthat occurs in CHF.

Role of Altered Chemoreflex in CHF:

As often happens in chronic disease states, chemoreflexes that arededicated under normal conditions to maintaining homeostasis andcorrecting hypoxia contribute to increase the sympathetic tone inpatients with CHF, even under normoxic conditions. The understanding ofhow abnormally enhanced sensitivity of the peripheral chemosensors,particularly the carotid body, contributes to the tonic elevation in SNAin patients with CHF has come from several studies in animals. Accordingto one theory, the local angiotensin receptor system plays a fundamentalrole in the enhanced carotid body chemoreceptor sensitivity in CHF. Inaddition, evidence in both CHF patients and animal models of CHF hasclearly established that the carotid body chemoreflex is oftenhypersensitive in CHF patients and contributes to the tonic elevation insympathetic function. This derangement derives from altered function atthe level of both the afferent and central pathways of the reflex arc.The mechanisms responsible for elevated afferent activity from thecarotid body in CHF are not yet fully understood.

Regardless of the exact mechanism behind the carotid bodyhypersensitivity, the chronic sympathetic activation driven from thecarotid body and other autonomic pathways leads to further deteriorationof cardiac function in a positive feedback cycle. As CHF ensues, theincreasing severity of cardiac dysfunction leads to progressiveescalation of these alterations in carotid body chemoreflex function tofurther elevate sympathetic activity and cardiac deterioration. Thetrigger or causative factors that occur in the development of CHF thatsets this cascade of events in motion and the time course over whichthey occur remain obscure. Ultimately, however, causative factors aretied to the cardiac pump failure and reduced cardiac output. Accordingto one theory, within the carotid body, a progressive and chronicreduction in blood flow may be the key to initiating the maladaptivechanges that occur in carotid body chemoreflex function in CHF.

There is sufficient evidence that there is increased peripheral andcentral chemoreflex sensitivity in heart failure, which is likely to becorrelated with the severity of the disease. There is also some evidencethat the central chemoreflex is modulated by the peripheral chemoreflex.According to current theories, the carotid body is the predominantcontributor to the peripheral chemoreflex in humans; the aortic bodyhaving a minor contribution.

Although the mechanisms responsible for altered central chemoreflexsensitivity remain obscure, the enhanced peripheral chemoreflexsensitivity can be linked to a depression of nitric oxide production inthe carotid body affecting afferent sensitivity, and an elevation ofcentral angiotensin II affecting central integration of chemoreceptorinput. The enhanced chemoreflex may be responsible, in part, for theenhanced ventilatory response to exercise, dyspnea, Cheyne-Stokesbreathing, and sympathetic activation observed in chronic heart failurepatients. The enhanced chemoreflex may be also responsible forhyperventilation and tachypnea (e.g., fast breathing) at rest andexercise, periodic breathing during exercise, rest and sleep,hypocapnia, vasoconstriction, reduced peripheral organ perfusion andhypertension.

Dyspnea:

Shortness of breath, or dyspnea, is a feeling of difficult or laboredbreathing that is out of proportion to the patient's level of physicalactivity. It is a symptom of a variety of different diseases ordisorders and may be either acute or chronic. Dyspnea is the most commoncomplaint of patients with cardiopulmonary diseases.

Dyspnea is believed to result from complex interactions between neuralsignaling, the mechanics of breathing, and the related response of thecentral nervous system. A specific area has been identified in themid-brain that may influence the perception of breathing difficulties.

The experience of dyspnea depends on its severity and underlying causes.The feeling itself results from a combination of impulses relayed to thebrain from nerve endings in the lungs, rib cage, chest muscles, ordiaphragm, combined with the perception and interpretation of thesensation by the patient. In some cases, the patient's sensation ofbreathlessness is intensified by anxiety about its cause. Patientsdescribe dyspnea variously as unpleasant shortness of breath, a feelingof increased effort or tiredness in moving the chest muscles, a panickyfeeling of being smothered, or a sense of tightness or cramping in thechest wall.

The four generally accepted categories of dyspnea are based on itscauses: cardiac, pulmonary, mixed cardiac or pulmonary, and non-cardiacor non-pulmonary. The most common heart and lung diseases that producedyspnea are asthma, pneumonia, COPD, and myocardial ischemia or heartattack (myocardial infarction). Foreign body inhalation, toxic damage tothe airway, pulmonary embolism, congestive heart failure (CHF), anxietywith hyperventilation (panic disorder), anemia, and physicaldeconditioning because of sedentary lifestyle or obesity can producedyspnea. In most cases, dyspnea occurs with exacerbation of theunderlying disease. Dyspnea also can result from weakness or injury tothe chest wall or chest muscles, decreased lung elasticity, obstructionof the airway, increased oxygen demand, or poor pumping action of theheart that results in increased pressure and fluid in the lungs, such asin CHF.

Acute dyspnea with sudden onset is a frequent cause of emergency roomvisits. Most cases of acute dyspnea involve pulmonary (lung andbreathing) disorders, cardiovascular disease, or chest trauma. Suddenonset of dyspnea (acute dyspnea) is most typically associated withnarrowing of the airways or airflow obstruction (bronchospasm), blockageof one of the arteries of the lung (pulmonary embolism), acute heartfailure or myocardial infarction, pneumonia, or panic disorder.

Chronic dyspnea is different. Long-standing dyspnea (chronic dyspnea) ismost often a manifestation of chronic or progressive diseases of thelung or heart, such as COPD, which includes chronic bronchitis andemphysema. The treatment of chronic dyspnea depends on the underlyingdisorder. Asthma can often be managed with a combination of medicationsto reduce airway spasms and removal of allergens from the patient'senvironment. COPD requires medication, lifestyle changes, and long-termphysical rehabilitation. Anxiety disorders are usually treated with acombination of medication and psychotherapy.

Although the exact mechanism of dyspnea in different disease states isdebated, there is no doubt that the CBC plays some role in mostmanifestations of this symptom. Dyspnea seems to occur most commonlywhen afferent input from peripheral receptors is enhanced or whencortical perception of respiratory work is excessive.

Surgical Removal of the Glomus and Resection of Carotid Body Nerves:

A surgical treatment for asthma, removal of the carotid body or glomus(glomectomy), was described by Japanese surgeon Komei Nakayama in 1940s.According to Nakayama in his study of 4,000 patients with asthma,approximately 80% were cured or improved six months after surgery and58% allegedly maintained good results after five years. Komei Nakayamaperformed most of his surgeries while at the Chiba University duringWorld War II. Later in the 1950's, a U.S. surgeon, Dr. Overholt,performed the Nakayama operation on 160 U.S. patients. He felt itnecessary to remove both carotid bodies in only three cases. He reportedthat some patients feel relief the instant when the carotid body isremoved, or even earlier, when it is inactivated by an injection ofprocaine (Novocain).

Overholt, in his paper Glomectomy for Asthma published in Chest in 1961,described surgical glomectomy the following way: “A two-inch incision isplaced in a crease line in the neck, one-third of the distance betweenthe angle of the mandible and clavicle. The platysma muscle is dividedand the sternocleidomastoid retracted laterally. The dissection iscarried down to the carotid sheath exposing the bifurcation. Thesuperior thyroid artery is ligated and divided near its take-off inorder to facilitate rotation of the carotid bulb and expose the medialaspect of the bifurcation. The carotid body is about the size of a grainof rice and is hidden within the adventitia of the vessel and is of thesame color. The perivascular adventitia is removed from one centimeterabove to one centimeter below the bifurcation. This severs connectionsof the nerve plexus, which surrounds the carotid body. The dissection ofthe adventitia is necessary in order to locate and identify the body. Itis usually located exactly at the point of bifurcation on its medialaspect. Rarely, it may be found either in the center of the crotch or onthe lateral wall. The small artery entering the carotid body is clamped,divided, and ligated. The upper stalk of tissue above the carotid bodyis then clamped, divided, and ligated.”

In January 1965, the New England Journal of Medicine published a reportof 15 cases in which there had been unilateral removal of the cervicalglomus (carotid body) for the treatment of bronchial asthma, with noobjective beneficial effect. This effectively stopped the practice ofglomectomy to treat asthma in the U.S.

Winter developed a technique for separating nerves that contribute tothe carotid sinus nerves into two bundles, carotid sinus (baroreflex)and carotid body (chemoreflex), and selectively cutting out the latter.The Winter technique is based on his discovery that carotid sinus(baroreflex) nerves are predominantly on the lateral side of the carotidbifurcation and carotid body (chemoreflex) nerves are predominantly onthe medial side.

Neuromodulation of the Carotid Body Chemoreflex:

Hlavaka in U.S. Patent Application Publication 2010/0070004 filed Aug.7, 2009, describes implanting an electrical stimulator to applyelectrical signals, which block or inhibit chemoreceptor signals in apatient suffering dyspnea. Hlavaka teaches that “some patients maybenefit from the ability to reactivate or modulate chemoreceptorfunctioning.” Hlavaka focuses on neuromodulation of the chemoreflex byselectively blocking conduction of nerves that connect the carotid bodyto the CNS. Hlavaka describes a traditional approach of neuromodulationwith an implantable electric pulse generator that does not modify oralter tissue of the carotid body or chemoreceptors.

The central chemoreceptors are located in the brain and are difficult toaccess. The peripheral chemoreflex is modulated primarily by carotidbodies that are more accessible. Previous clinical practice had verylimited clinical success with the surgical removal of carotid bodies totreat asthma in 1940s and 1960s.

Additional Exemplary Embodiments

-   1. A method for ablating the function of a carotid body in a patient    comprising:    -   a. locating a region in a patient including a carotid body,    -   b. inserting into the patient a cryo-ablation device comprising        an elongated body having a distal region and a proximal region,        the distal region includes a cryo-ablation element;    -   c. advancing the distal region of said cryo-ablation device        through the body of the patient;    -   d. positioning the distal region of the cryo-ablation device        proximate to the region containing the carotid body;    -   e. ablating tissue in the region that includes the carotid body        by cooling the region with the cryo-ablation element;    -   f. withdrawing the cryo-ablation device from the patient.-   2. The method of claim 1 wherein the step of locating includes    defining a three-dimensional region of a carotid septum.-   3. The method of claim 2 wherein the carotid septum is a triangular    segment having boundaries at a saddle of a carotid bifurcation,    sidewalls defined by an internal carotid artery and an external    carotid artery, and a base extending between the internal and    external carotid arteries.-   4. The method of claim 3 wherein the base is within 15 mm of the    saddle.-   5. The method of claims 3 and 4 wherein the boundaries of the    carotid septum include a first plane tangent to the lateral walls of    the internal and external carotid arteries and a second plane    tangent to the medial walls of the internal and external carotid    arteries.-   6. The method of claim 1 wherein the cryo-ablation device comprises    a vascular catheter.-   7. The method of claims 1 to 6 wherein the cryo-ablation device is    advanced through the vascular system of the patient.-   8. The method of claims 1 to 5 wherein the cryo-ablation device    comprises a percutaneous probe.-   9. The method of claim 8 wherein the cryo-ablation device is    advanced through the neck of the patient.-   10. The method of claims 1 to 5 further comprising determining a    value of a parameter associated with the cooling by the    cryo-ablation element, and using the value to set the cooling by    said cryo-ablation device.-   11. The method of claim 10 wherein a parameter is cryo-ablation    element temperature.-   12. The method of claim 10 wherein a parameter is duration of    cooling.-   13. The method of claim 10 wherein a parameter is cryo-ablation    element contact force.-   14. The method of claim 10 wherein a parameter is number of cooling    cycles.-   15. The method of claim 10 wherein a parameter is the location of    the cryo-ablation element within the patient.-   16. The method of any claims 1 to 15 wherein cooling results in    tissue temperature below zero degrees centigrade within the region    including the carotid body.-   17. The method of claim 16 wherein tissue temperatures below zero    degrees centigrade is substantially limited to said region.-   18. The method of claim 1 further comprising placing upon the body    of the patient an ultrasonic imaging device configured for imaging    the region including a carotid body.-   19. The method of claim 18 wherein the ultrasonic imaging device is    configured for extracorporeal imaging.-   20. The method of claim 18 wherein the ultrasonic imaging device is    configured for intravascular imaging.-   21. The method of any claims 18 to 20 wherein the ultrasonic imaging    device is configured to image a boundary between frozen tissue and    not frozen tissue.-   22. The method of claims 18 to 21 wherein at least one cryo-ablation    parameter is adjusted based on an imaged spatial relationship    between the boundary of the frozen and not frozen tissue, and the    boundary of said region.-   23. The method of claim 1 further comprising placing an embolization    protection device into an internal carotid artery prior to the    ablation.-   24. The method of claim 1 wherein the means for locating the region    including a carotid body comprises an imaging study.-   25. The method of claim 24 wherein the size of the carotid body is    determined.-   26. The method of claims 24 and 25 wherein the imaging study    comprises Computed Tomography Angiography.-   27. The method of claims 24 and 25 wherein the imaging study    comprises MR Angiography.-   28. The method of claims 24 and 25 wherein the imaging study    comprises Fluoroscopic Angiography.-   29. The method of claims 24 and 25 wherein the imaging study    comprises sonography.-   30. The method of claim 1 wherein the function of a carotid body is    stimulated.-   31. The method of claim 30 wherein the stimulation comprises    application of electrical energy to the region including the carotid    body.-   32. The method of claim 30 wherein the stimulation comprises    administration of a chemical agent.-   33. The method of claim 30 wherein the stimulation comprises a    manipulation in the composition of inhaled gas-   34. The method of any of claims 30 to 33 wherein the carotid body is    stimulated prior to said ablation and after said ablation.-   35. The method of claim 1 wherein the function of a carotid body is    blocked.-   36. The method of claim 35 wherein the blockade comprises    application of electrical energy to the region including the carotid    body.-   37. The method of claim 35 wherein the blockade comprises    administration of a chemical agent.-   38. The method of claim 35 wherein the blockade comprises a    manipulation in the composition of inhaled gas-   39. The method of any of claims 35 to 38 wherein the carotid body is    blocked prior to said ablation and after said ablation.-   40. The method of claim 1 further comprising steps b through e    repeated with the cryo-ablation element placed in at least one    additional location.-   41. The method of either of claims 1 and 40 further comprising    repeating steps b through e with the cryo-ablation element at the    same location.-   42. The method of any claims 1 to 41 wherein the cryo-ablation    element comprises a temperature sensor.-   43. The method of claim 42 wherein the temperature sensor is    connected to a source of cry-ablation fluid by electrical wires    within the body of the cryo-ablation device.-   44. The method of claims 42 and 43 wherein the temperature sensor is    configured for controlling the source of cryo-ablation fluid in    order to maintain the cryo-ablation element at a selected    cryo-ablation temperature.-   45. The method of claims 6 and 7 wherein the wherein the functional    length of the catheter is greater than 90 cm.-   46. The method of claims 6 and 7 wherein the catheter comprises a    lumen configured for use with a standard guide wire.-   47. The method of claim 46 wherein the guide wire is between 0.014″    and 0.038: diameter.-   48. The method of any claims 6, 7, 44 through 47 wherein the    catheter comprises a braided shaft.-   49. The method of any claims 6, 7, 44 through 48 wherein the    catheter comprises a deflectable longitudinal segment in the region    of the distal end, and a non-deflectable longitudinal segment    immediately proximal to said deflectable segment.-   50. The method of claim 49 wherein the deflectable longitudinal    segment is configured for user actuation by means of an internal    pull wire in communication with the distal end of the catheter and a    handle in the vicinity of the proximal end of the catheter    comprising an actuator.-   51. The method of claims 49 and 50 wherein the length of the    deflectable longitudinal segment is between 5 mm and 18 mm long.-   52. The method of any claims 49 through 51 wherein the actuator is    configured to apply a predetermined force of contact between the    cryo-ablation element and a vascular wall.-   53. The method of claim 6 wherein the catheter comprises at least    one electrode in the region of the distal end.-   54. The method of claims 6 and 53 wherein the cryo-ablation element    is further configured as an electrode.-   55. The method of claims 53 and 54 wherein the electrode(s) is    configured to electrically stimulate carotid body function.-   56. The method of any claims 53 through 55 wherein the electrode(s)    is configured to electrically block carotid body function.-   57. The method of any claims 53 through 56 wherein the electrode(s)    is connectable to a source of electrical energy by means of an    electrical conducting wire(s) located within the catheter between    the electrode(s) and an electrical connector located in the region    of the proximal end of the catheter.-   58. The method of claim 1 wherein the cryo-ablation element    comprises a cryogenic chamber.-   59. The method of claim 58 wherein the cryogenic chamber comprises a    liquid refrigerant evaporation chamber-   60. The method of claims 58 and 59 wherein the cryogenic chamber    comprises a cryogenic gas expansion chamber.-   61. The method of claim 58 wherein the ablation element temperature    is preselected in a range of 0 Deg. C. to −180 Deg. C.-   62. The method of any claims 10 to 17 wherein the parameters of    cryo-ablation are selected for reversible ablation.-   63. The method of claim 62 wherein the reversible ablation results    in a physiological response predictive of a permanent ablation.-   64. The method of claim 63 wherein the physiological response is    indicative of a carotid body ablation.-   65. The method of claims 62 to 64 wherein the physiological response    is a change in at least one physiological parameter comprising heart    rate, heart rate variability, respiration rate, respiration volume,    and blood pressure.-   66. The method of claim 62 wherein the reversible ablation results    in a physiological response indicative of an undesirable ablation    effect.-   67. The method of claim 66 wherein the physiological response is    indicative of an ablation of at least one vital nervous structure    comprising a vagal nerve, a sympathetic nerve, a hypoglossal nerve    or a baroreflex nervous structure.-   68. The method of any claims 62 to 67 wherein parameters for    permanent ablation are selected in part based on the physiological    response to the reversible ablation.-   69. The method of any claims 62 to 68 wherein a permanent ablation    is performed following a reversible ablation.-   70. The method of claim 6 wherein the catheter comprises a balloon    at the level of the cryo-ablation element.-   71. The method of claim 7 wherein the cryo-ablation element is held    in forced contact with the wall of a vascular structure in the    region including the carotid body by inflation of a balloon.-   72. The method of claims 70 and 71 wherein the balloon is inflated    to a predetermined pressure.-   73. The method of claims 70 to 72 wherein the balloon is inflated    with a gas configured to thermally insulate the cryo-ablation    element from vascular blood.-   74. The method of any claims 70 to 73 wherein the balloon is    substantially non-compliant.-   75. The method of any claims 70 to 74 wherein the balloon diameter    is preselected based on patient vascular anatomy.-   76. The method of claims 8 and 9 wherein the percutaneous probe is a    rigid needle structure.-   77. The method of claims 8 and 9 wherein the percutaneous probe is a    flexible structure configured for use with a percutaneous sheath.-   78. The method of claim 76 wherein the caliber of the percutaneous    probe is between 12 gage and 18 gage.-   79. The method of claim 77 wherein the caliber of the percutaneous    probe is between 4 French and 8 French.-   80. The method of any claims 76 to 79 wherein the functional length    of the percutaneous probe is at least 4 cm.-   81. A device for ablating the function of a carotid body comprising:    -   a. a vascular catheter configured for use in the vicinity of a        carotid artery bifurcation comprising a distal end and a        proximal end,    -   b. a cryo-ablation element disposed in the region of the distal        end;    -   c. a balloon adjacent to the cryo-ablation element;    -   d. a braided structure disposed within the wall of the catheter        between the distal end and the proximal end;    -   e. a connection between the cryo-ablation element and a source        of cryo-ablation fluid, and    -   f. a connection between the balloon and a balloon inflation        mechanism;    -   whereby, the balloon is configured for inflation and to apply a        contact force between the cryo-ablation element and the wall of        a vascular structure and to thermally insulate the cryo-ablation        element from vascular blood.-   82. The device of claim 81 wherein the catheter is configured for    use through a carotid access sheath no greater than 8 French.-   83. The device of any claims 81 and 82 wherein the working length of    the catheter is at least 90 cm.-   84. The device of any claims 81 to 83 wherein the catheter is    configured for use with a guide wire.-   85. The device of claim 84 wherein the guide wire is between 0.014″    to 0.038″ diameter.-   86. The device of claim 81 wherein the cryo-ablation element    comprises a cryo chamber.-   87. The device of claim 86 wherein the cryo-ablation chamber is    configured as a liquid evaporation chamber.-   88. The device of claim 86 wherein the cryo-ablation chamber is    configured as a gas expansion chamber.-   89. The device of any claims 86 to 88 wherein a temperature sensor    is associated with the cryo-ablation element.-   90. The device of claim 89 wherein the temperature sensor is    connectable to a source cryogenic fluid and configured to control    the source of cryogenic fluid and maintain the cryo-ablation element    at a selected temperature.-   91. The device of any claims 81 to 85 wherein the balloon is    fabricated from a compliant material.-   92. The device of any claims 81 to 85 wherein the balloon is    fabricated from a non-compliant material.-   93. The device of any claims 81 to 92 wherein the catheter is    manufactured with a user choice of balloon diameters between 3 mm    and 18 mm.-   94. The device of claim 81 further comprising at least one electrode    configured for electrical neural modulation.-   95. The device of claim 94 wherein the cryo-ablation element is    configured as an electrode.-   96. The device of claims 94 and 95 wherein the electrode(s) is    connectable to a source of electricity configured for neural    modulation.-   97. The device of claim 81 wherein the cryo-ablation element is    configured as an RF ablation electrode.-   98. The device of claim 97 wherein the cryo-ablation element is    connectable to a source of RF ablation energy.-   99. The device of any claims 81 to 98 further comprises at least one    radiopaque element disposed in the region of the distal end    configured to provide the user with an unambiguous fluoroscopic    indication of the position of the cryo-ablation element in a blood    vessel.-   100. A system for ablation carotid body function is a patient    comprising:    -   a. a vascular catheter configured for use in the vicinity of a        carotid bifurcation comprising a distal end and a proximal end,        a cryo-ablation element disposed in the region of the distal        end, a balloon adjacent to the cryo-ablation element, a braided        structure disposed within the wall of the catheter between the        distal end and the proximal end, a connection between the        cryo-ablation element and a source of cryo-ablation fluid, and a        connection between the balloon and a balloon inflation        mechanism,    -   b. a console comprising a source of cryo-ablation fluid, a means        for controlling said cryo-ablation fluid, a user interface        configured to provide the user with a selection of ablation        parameters, and to provide the user with indications of the        status of the console, and the status of ablation activity, and        a means to activate and deactivate an ablation,    -   c. an umbilical cable configured to connect the console to the        vascular catheter;    -   whereby, the vascular catheter provides the means of user        placement of the cryo-ablation element into an optimal position        within the vascular system for ablation of carotid body        function, and the console provides the user with a selection of        cryo-ablation parameters and supplies the cryo-ablation element        with cryo-ablation fluid.-   101. The system of claim 100 further comprises a means for    electrical neural modulation.-   102. The system of claim 100 further comprises a means for RF    ablation.-   103. The method of claim 7 wherein the cryo-ablation device is    advanced through the arterial system into a carotid artery.-   104. The method of claim 7 wherein the cryo-ablation device is    advanced through the venous system into an internal jugular vein.-   105. The method of claim 7 wherein the cryo-ablation catheter is    advanced through the venous system into a facial vein.-   106. A device for percutaneous cryo-ablation of the function of a    carotid body comprising:    -   a. a rigid hollow elongated structure having a distal region and        a proximal region;    -   b. a cryo-ablation element in the distal region;    -   c. a warming element distal to the cryo-ablation element;    -   d. a fluid connection between the cryo-ablation element and a        source of cryogenic fluid;    -   e. an electrical connection between the warming element and a        source of electrical warming energy.-   107. A method for percutaneous ablation of a carotid body    comprising:    -   a. determining a pathway void of vital structures between a        point on the neck of a patient and a region including a carotid        body;    -   b. inserting a needle into the patient through the pathway;    -   c. inserting a guide wire through the needle;    -   d. replacing the needle with a percutaneous sheath;    -   e. inserting a cryo-ablation probe into the region through the        sheath;    -   f. activating the cryo-ablation probe;    -   whereby, the function of the carotid body is substantially        diminished by the activation of the cryo-ablation probe.-   108. The method of claim 107 wherein the cryo-ablation probe    comprises a needle like structure with a cryo-ablation element in    the region of the distal tip.-   109. The method of claim 108 wherein the cryo-ablation probe    comprises a warming element at the distal tip configured to warm    tissue distal to the tip simultaneously with cryo-ablation.-   110. The method of claims 107 to 109 wherein the warming element is    activated in during cryo-ablation.-   111. The method of claim 110 wherein the temperature of the warming    element is maintained between zero and 42 degrees centigrade.-   112. The method of any claims 107 to 111 wherein the boundary    between frozen tissue and not frozen tissue is monitored by an    ultrasonic imaging device during cryo-ablation.-   113. The device of claim 106 wherein the warming element is    associated with a temperature sensor configured to control warming.-   114. The device of claims 106 and 113 wherein the cryo-ablation    element is associated with a temperature sensor configured to    control a cryo-ablation.-   115. The method of claim 109 wherein the warming element is    maintained at a determined temperature.-   116. The method of claim 109 wherein the warming element protects    vital nervous structures from cryo-ablation.-   117. A method for catheter-based chemoreceptor neuromodulation, the    method comprising:    -   a. positioning a catheter having a therapeutic cryogenic element        within an artery of a human patient; and    -   b. reducing neural traffic within the patient due to the        therapeutic cryogenic element,    -   wherein reducing the neural traffic therapeutically treats a        diagnosed condition of disease associated with autonomic        imbalance.-   118. A method for catheter-based chemoreceptor ablation, the method    comprising:    -   a. positioning a catheter having an cryogenic ablation element        within an artery of a human patient; and    -   b. reducing chemoreceptor neural traffic within the patient due        to the cryogenic ablation element,    -   wherein reducing the chemoreceptor neural traffic        therapeutically treats a diagnosed condition of disease        associated with autonomic imbalance.-   119. A method for treating a patient comprising:    -   a. locating a region in the patient including a carotid body,    -   b. inserting into the patient a cryogenic ablation device, said        cryogenic ablation device comprising a distal region and a        proximal region, an ablation element mounted to said distal        region, a connection extending through the cryogenic ablation        device from the distal region to the proximal region wherein a        cryogen is delivered to the proximal region through the        connection to the ablation element;    -   c. positioning the distal region in the vascular structure at a        location proximate to said carotid body region, wherein the        ablation element abuts a wall of said vascular structure;    -   d. while the ablation element abuts the wall, transferring heat        energy from said ablation device to the wall or from the wall to        the ablation device to ablate tissue in the region that includes        the carotid body, and    -   e. withdrawing the ablation device from the patient.-   120. A device for catheter-based carotid body cryo-ablation, the    device comprising:    -   a. an elongated structure having distal region and a proximal        region and a lumen running between;    -   b. a cryo-ablation element in the distal region having two        deployable arms; and    -   c. a means for transporting cryogen through the lumen from the        proximal region to the cryo-ablation element and along the        deployable arms.-   121. A device of claim 120 wherein the cryogen is maintained at a    near critical point and the means for transporting cryogen is two    cryogen delivery tubes passing within the lumen and along the two    deployable arms and returned to the proximal region in two cryogen    return tubes.-   122. A device of claim 120 wherein the deployable arms comprise    Nitinol strips having preformed bends configured to deploy the    cryo-ablation element into a V-shape.

What is claimed is:
 1. A method for cryo-ablating target tissue within acarotid septum of a patient, the method comprising: advancing a ballooncatheter towards a bifurcation of an internal carotid artery and anexternal carotid artery of a patient, the balloon catheter comprising afirst arm and an expandable balloon, passing the first arm into theinternal carotid artery and engaging the first arm with the carotidartery bifurcation; passing the balloon into the external carotid arteryand expanding the balloon; advancing a cryo-ablation catheter supportinga cryo-ablation element out of an exit port in the catheter such thatthe cryo-ablation element is disposed adjacent the carotid septum; andactuating the cryo-ablation element to ablate at least a portion of thecarotid septum.
 2. The method of claim 1 further comprising retracting asheath to cause the first arm to assume a preformed configuration inwhich it extends from an axis of the balloon catheter at between about30 and about 60 degrees.
 3. The method of claim 1 wherein advancing acryo-ablation catheter out of an exit port comprises advancing acryo-ablation catheter out of a side exit port in the catheter.
 4. Themethod of claim 3 further comprising engaging the cryo-ablation elementwith the wall of the external carotid artery.
 5. The method of claim 1wherein advancing a cryo-ablation catheter out of an exit port comprisesadvancing a cryo-ablation catheter out of an exit port in the catheterand into the interior of the expandable balloon.
 6. The method of claim5 further comprising engaging the cryo-ablation element into contactwith interior of the balloon wall.
 7. A method for cryo-ablating targettissue within a carotid septum of a patient, the method comprising:advancing a cryo-ablation catheter into an artery of a patient, thecryo-ablation device comprising first and second arms; passing the firstarm into an external carotid artery of the patient and into engagementwith a wall of the external carotid artery adjacent a carotid septum;passing the second arm into an internal carotid artery of the patientand into engagement with a wall of the internal carotid artery adjacentthe carotid septum; and delivering a cryogen fluid through the first andsecond arms to ablate at least a portion of the carotid septum.
 8. Themethod of claim 7 wherein advancing a cryo-ablation catheter into anartery of a patient comprises advancing the first and second arms incollapsed delivery configurations.
 9. The method of claim 7 furthercomprising retracting a sheath to cause the first and second arms todeploy to preformed delivery configurations.
 10. A method forcryo-ablating target tissue within a carotid septum of a patient, themethod comprising: advancing an expandable balloon into a vesseladjacent a carotid septum and expanding the balloon into contact withthe vessel; positioning a cryoablation element within the vesseladjacent the carotid septum; and cryoablating tissue in the carotidseptum using the cryoablation element.
 11. A carotid septum ablationcatheter, comprising: a deployable arm and an expandable balloondisposed at a distal region of the catheter, the catheter adapted andconfigured to support a cryoablation element, wherein the deployable armis configured to engage a wall of an internal carotid artery when theexpandable balloon and cryoablation element are disposed in an externalcarotid artery.
 12. A cryo-ablation catheter adapted to be advancedtowards a bifurcation of an internal carotid artery and an externalcarotid artery, comprising: a first arm configured to engage with a wallof the internal carotid artery delimiting a carotid septum, and a secondarm configured to be simultaneously engaged with a wall of the externalcarotid artery delimiting the carotid septum, the first and second armsconfigured to carry a cryogen fluid to ablate at least a portion of thecarotid septum.